IndraLab
Statements
ATXN3 is modified
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ATXN3 is ubiquitinated.
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sparser
"We explored this notion in this study and present evidence that: (a) the C-terminus of ataxin-3 isoform 2 signals its degradation in a proteasome-dependent manner, (b) this effect from the C-terminus of isoform 2 does not require the ubiquitination of ataxin-3, and (c) the isolated C-terminus of isoform 2 can enhance the degradation of an unrelated protein."
sparser
"In these latter studies ubiquitination, including on K117, did not increase the degradation of ataxin-3; instead, the proposed mechanism was one whereby ubiquitinated ataxin-3 is more active as an enzyme and able to better protect against polyQ toxicity by enhancing the production of heat shock proteins ( xref , xref ; xref )."
ATXN3 is phosphorylated.
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"Phosphorylation has also been implicated in influencing the toxicity of SCA3, DRPLA and SBMA, for example: phosphorylation of ataxin-3 at S256 by glycogen synthase kinase 3β reduces aggregation of polyglutamine-expanded atxain-3 xref ; phosphorylation of polyglutamine-expanded androgen receptor by MAPK at S516 is associated with increased cleavage and toxicity in cell models of SBMA xref ; and S734 of atrophin-1 is phosphorylated by Jun-N-terminal kinase, although the significance of this in the pathogenesis of DRPLA has not yet been examined."
rlimsp
"We report that S12 of ataxin-3 is phosphorylated in neurons and that mutating this residue so as to mimic a constitutive phosphorylated state counters the neuromorphologic defects observed. In rats stereotaxically injected with expanded ataxin-3-encoding lentiviral vectors, mutation of serine 12 reduces aggregation, neuronal loss, and synapse loss. Our results suggest that S12 plays a role in the pathogenic pathways mediated by polyglutamine-expanded ataxin-3 and that phosphorylation of this residue protects against toxicity."
ATXN3 is sumoylated.
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ATXN3 activates ATXN3.
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ATXN3 inhibits ATXN3.
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"The specific mechanism through which calpain inhibitor treatments increase autophagic activity in our transgenic zebrafish model of SCA3 is yet to be fully elucidated.These findings indicate that treatment with BLD-2736 may produce beneficial effects in SCA3 zebrafish via either decreasing cleavage of the ataxin-3 protein and/or increased autophagic clearance of any neurotoxic ataxin-3 protein aggregates."
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"Phosphorylations of ATX3 by protein casein kinase 2 (CK2) stimulate SCA3 pathogenesis by altering its stability, nuclear localization, and inclusion formation [50,51], while GSK3β-mediated phosphorylation inhibits ATX3 aggregation which has a protective role in SCA3 pathophysiology [94]."
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"Recently, treatment of a C. elegans model of SCA3 (spinocerebellar ataxia type 3; also known as Machado-Joseph disease) with 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor, successfully decreased the mutant ATXN3 aggregation and improved locomotor activity [XREF_BIBR]."
ATXN3 decreases the amount of ATXN3.
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3
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"The simultaneous upregulation of closely related miRNAs targeting the 3 ' UTR of ATXN3 correlates with significantly reduced ATXN3 expression levels in SCA3-LCs suggesting that members of the miR-25 and miR-181 family cooperatively bind to the 3 ' UTR of ATXN3 to suppress the expression of ATXN3 in SCA3-LCs."
sparser
"The PLA analysis showed no significant interaction of ATXN3 with DNA LIG 3α in the brain sections from SCA3 patients, or in control brains under identical experimental conditions ( xref ; panels 1 and 4), suggesting specificity of the interactions between ATXN3 and PNKP in vivo ."
sparser
"To examine ATXN3’s association with PNKP, we immunoprecipitated (IP’d) PNKP and ATXN3 separately from the nuclear extract (NE, benzonase treated to remove DNA and RNA to avoid DNA-mediated co-immunoprecipitation) of human HEK-293 (human embryonic kidney cell line) ( xref ) and SH-SY5Y (a human neuroblastoma cell line) cells ( xref ) using the respective anti-protein (PNKP or ATXN3) antibody (Ab)."
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"In the present study, we show that the essential DNA strand break repair enzyme PNKP (polynucleotide kinase 3 '-phosphatase) interacts with, and is inactivated by, the mutant ATXN3, resulting in inefficient DNA repair, persistent accumulation of DNA damage and strand breaks, and subsequent chronic activation of the DNA damage response ataxia telangiectasia mutated (ATM) signaling pathway in SCA3."
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"In contrast, mutant ATXN3 interacts with PNKP and abrogates its 3 '-phosphatase activity, resulting in increased accumulation of DNA damage that chronically activates ATM --> p53 and ATM --> c-Abl --> PKCdelta pro apoptotic signaling to trigger neuronal dysfunction and apoptosis in SCA3 (illustrated in XREF_FIG)."
Alzheimer Disease affects ATXN3
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ATXN3 binds Alzheimer Disease. 10 / 81
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"Since the discovery of rare early-onset autosomal dominant familial forms of AD caused by missense mutations of the APP gene within the Aβ region, synthetic peptides bearing familial and design mutations have been used to investigate the potential importance of primary sequence in determining Aβ aggregation, toxicity and synaptic disruption [ xref ]."
sparser
"Autosomal dominant forms of AD are due to mutations in the amyloid precursor protein (APP) [ xref , xref ], the protein from which the Aβ peptide present in amyloid plaques is derived, increased copy number for APP, and mutations in Presenilin 1 and 2, whose protein products regulate processing of APP [ xref , xref ]."
APP binds ATXN3 and Alzheimer Disease. 2 / 2
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"The mammalian protein CHIP is a U-box domain-containing cytosolic PQC E3 ligase that facilitates the degradation of misfolded proteins with the help of chaperones HSP70 or HSP90. xref In the heart, CHIP has a strong cardioprotective effect, as demonstrated by inhibition of apoptosis following I/R injury, xref angiotensin II-induced cardiac remodeling, xref and myocardial infarction. xref It was recently found that monoubiquitination of CHIP by an E2 enzyme Ube2w promotes the interaction of CHIP with Ataxin-3, a deubiquitinating enzyme (DUB)."
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"Whether CHIP is the primary mediator of ubiquitin dependent degradation of ataxin-3 is controversial : XREF_BIBR reported that CHIP ubiquitinates ataxin-3 and directs it to the proteasome for degradation, whereas XREF_BIBR reported that another ubiquitin ligase, E4B, mediates ataxin-3 degradation while CHIP has no effect."
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"Flow cytometry analysis using Annexin V-FITC and propidium iodide (PI) staining in HCT116 cells showed that knockdown of ATX-3 led to a decrease of camptothecin (CPT)-induced apoptosis, while ectopic expression of ATX-3 but not the catalytic inactive mutant ATX-3-C14A resulted in a significant increase of apoptosis in HCT116 p53 +/+ but not HCT116 p53 -/- cells (XREF_FIG), indicating that ATX-3 promoted p53 mediated apoptosis, which required its deubiquitinating enzymatic activity."
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"Besides, we found that the degradation of p53 in the ATX-3 exp (80Q)-expressing cells was slower than that of normal ATX-3-expressing cells (XREF_SUPPLEMENTARY), and ectopic expression of polyQ expanded ATX-3 induced higher levels of p53 protein than the normal ATX-3 in RKO, 293T, and MEF cells (XREF_SUPPLEMENTARY), indicating that polyQ expanded ATX-3 possessed enhanced capability to stabilize p53."
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"Consistent with our hypothesis, ATXN3-Q84 expression failed to stimulate phosphorylation of Chk2 and p53 in the presence of the ATM inhibitor Ku55933 (XREF_SUPPLEMENTARY), substantiating our interpretation that mutant ATXN3 stimulates the DNA damage response p53 pathway via activating ATM."
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"Not only in primary cultures of central nervous cells expressing mutant ataxin-3 but also in pontine nuclei of SCA3 transgenic mice, mutant ataxin-3 can increase the expression of total and phosphorylated p53 as well as the transcriptional activity of p53, which is associated with upregulation of Bax and activated caspase-3 and 9 expression and subsequent apoptotic cell death XREF_BIBR, XREF_BIBR."
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"For example, the HAT CBP also acts as a CREB binding protein and can take part in transcriptional dysfunction in HD, whereas post-translational modification affects transcriptional regulation, mutant ataxin-3 and mutant ataxin-7 could cause phosphorylation and ubiquitination of p53, resulting in p53 transcriptional regulation."
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"ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription and expression of p53 target genes and promotes p53 dependent apoptosis in both mammalian cells and the central nervous system of zebrafish."
sparser
"The mammalian protein CHIP is a U-box domain-containing cytosolic PQC E3 ligase that facilitates the degradation of misfolded proteins with the help of chaperones HSP70 or HSP90. xref In the heart, CHIP has a strong cardioprotective effect, as demonstrated by inhibition of apoptosis following I/R injury, xref angiotensin II-induced cardiac remodeling, xref and myocardial infarction. xref It was recently found that monoubiquitination of CHIP by an E2 enzyme Ube2w promotes the interaction of CHIP with Ataxin-3, a deubiquitinating enzyme (DUB)."
"Indeed, ataxin-3 not only deubiquitinated CHIP, but also trimmed Ub conjugates on CHIP substrates, thereby regulating the length of Ub chains."
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"Importantly, ataxin-3 deubiquitinates CHIP, terminating CHIP-substrate interaction; polyQ expansion of ataxin-3 increases its affinity for CHIP and decreases CHIP levels in SCA3 mice, suggesting a surprising role for coordinated regulation of CHIP and ataxin-3 as well as dysregulation of this process in SCA3."
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"Evidence further supporting this notion that the ability of ataxin-3 to deubiquitinate CHIP is coupled to the ligase activity of CHIP, came from assays in which ataxin-3-mediated deubiquitination of CHIP did not occur until after poly-Ub conjugates on substrate proteins had attained a certain length."
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"To determine whether deubiquitination of Ub-CHIP by ataxin-3 requires the presence of ubiquitinated substrate, we performed CHIP ubiquitination reactions with increasing concentrations of HSP90 as substrate, in the presence or absence of ataxin-3 and the chain elongating E2, UbcH5c (XREF_FIG), then assessed the ubiquitin state of CHIP at the end of the reaction."
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"Importantly, ataxin-3 deubiquitinates CHIP, terminating CHIP-substrate interaction; polyQ expansion of ataxin-3 increases its affinity for CHIP and decreases CHIP levels in SCA3 mice, suggesting a surprising role for coordinated regulation of CHIP and ataxin-3 as well as dysregulation of this process in SCA3."
sparser
"Two major full-length isoforms of ataxin-3 exist, both of which contain the same N-terminal portion and polyQ repeat, but differ in their C-termini; one (denoted here as isoform 1) contains a motif that binds ataxin-3’s substrate, ubiquitin, whereas the other (denoted here as isoform 2) has a hydrophobic tail."
sparser
"In fact, higher levels of Ub-Rheb were co-IPed with ATXN3 when N-Ethylmaleimide, a deubiquitinase inhibitor, was included in the lysis and purification buffers ( xref ), supporting the idea that the Ub-Rheb that binds to ATXN3 was subjected to deubiquitination during the isolation processes."
sparser
"The PLA analysis showed no significant interaction of ATXN3 with DNA LIG 3α in the brain sections from SCA3 patients, or in control brains under identical experimental conditions ( xref ; panels 1 and 4), suggesting specificity of the interactions between ATXN3 and PNKP in vivo ."
sparser
"To examine ATXN3’s association with PNKP, we immunoprecipitated (IP’d) PNKP and ATXN3 separately from the nuclear extract (NE, benzonase treated to remove DNA and RNA to avoid DNA-mediated co-immunoprecipitation) of human HEK-293 (human embryonic kidney cell line) ( xref ) and SH-SY5Y (a human neuroblastoma cell line) cells ( xref ) using the respective anti-protein (PNKP or ATXN3) antibody (Ab)."
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"In the present study, we show that the essential DNA strand break repair enzyme PNKP (polynucleotide kinase 3 '-phosphatase) interacts with, and is inactivated by, the mutant ATXN3, resulting in inefficient DNA repair, persistent accumulation of DNA damage and strand breaks, and subsequent chronic activation of the DNA damage response ataxia telangiectasia mutated (ATM) signaling pathway in SCA3."
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"In contrast, mutant ATXN3 interacts with PNKP and abrogates its 3 '-phosphatase activity, resulting in increased accumulation of DNA damage that chronically activates ATM --> p53 and ATM --> c-Abl --> PKCdelta pro apoptotic signaling to trigger neuronal dysfunction and apoptosis in SCA3 (illustrated in XREF_FIG)."
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"In support of our idea that S345 phosphorylation is involved in regulating the interaction between ATX3 and Chk1 after persistent replication stress, the decreased association between ATX3 and Chk1 under replicative stress was restrained when Chk1 S345 phosphorylation was inhibited by CGK733, an inhibitor of ATM and ATR."
"Taken together, these findings reveal ATX3 to be a novel deubiquitinase of Chk1, providing a new mechanism of Chk1 stabilization in genome integrity maintenance."
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"We discover that, under unperturbed conditions and upon DNA damage, deubiquitination of Chk1 by ATX3 limits its polyubiquitination and subsequent degradation mediated by CUL1- and CUL4A- containing E3 ligase complexes, thus promoting Chk1 stabilization and further checkpoint signaling and DNA repair."
sparser
"Two major full-length isoforms of ataxin-3 exist, both of which contain the same N-terminal portion and polyQ repeat, but differ in their C-termini; one (denoted here as isoform 1) contains a motif that binds ataxin-3’s substrate, ubiquitin, whereas the other (denoted here as isoform 2) has a hydrophobic tail."
sparser
"In fact, higher levels of Ub-Rheb were co-IPed with ATXN3 when N-Ethylmaleimide, a deubiquitinase inhibitor, was included in the lysis and purification buffers ( xref ), supporting the idea that the Ub-Rheb that binds to ATXN3 was subjected to deubiquitination during the isolation processes."
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"AT3 is composed of a structured globular N-terminal domain, the Josephin domain (JD), which displays ubiquitin hydrolase activity, followed by a disordered C-terminal tail containing two ubiquitin interacting motifs (UIMs) and the polyQ stretch of variable length, whose expansion beyond a certain threshold triggers SCA3 [XREF_BIBR, XREF_BIBR]."
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"The research results from the Scaglione KM group demonstrate that the ubiquitin conjugating enzyme UBE2W attaches ubiquitin to the N-terminus of ataxin-3 and directs ubiquitin-degradation of ataxin-3 [24], suggesting that ubiquitin E2 enzyme may also directly bind to the substrate and promote its degradation."
ATXN3 affects cell death
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ATXN3 activates cell death.
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ATXN3 activates cell death. 10 / 29
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"In a SCA 3 cell model, the expression of a fragment of ataxin-3 containing an elongated polyQ stretch induced apoptosis and cell death as well as a severe ataxia in a mouse model, showing a more rapid manifestation of a SCA 3-reminiscent phenotype when compared to mice expressing full length mutant ataxin-3 [XREF_BIBR]."
Mutated ATXN3 activates cell death. 6 / 6
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ATXN3 inhibits cell death.
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ATXN3 inhibits cell death. 4 / 7
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"These results are in complete agreement with previous reports showing that both depletion of ATXN3 and overexpression of pathogenic polyQ ATXN3 alleles caused disorganization of cytoskeleton and increased cell death in cultured cells (Neves-Carvalho et al., 2015; Rodrigues et al., 2010)."
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"In our cellular model, full-length expanded ataxin-3 that leads to neurodegenerative disorders significantly impaired the expression of Bcl-2 protein, which may be, at least in part, responsible for the weak tolerance to polyglutamine toxicity at the early stage of disease and ultimately resulted in an increase of stress induced cell death upon apoptotic stress."
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ATXN3 translocates.
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"Recent work in our lab demonstrated that Atxn3 responded to select proteotoxic stresses by altering its interactions with two shuttle proteins that function in protein degradation, valosin-containing protein (VCP/p97) and human Rad23 (HR23B); furthermore, in response to heat shock and oxidative stress Atxn3 translocated to the nucleus (Reina et al. xref )."
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"Because our data show that Atx3 can also be exported from the nucleus and that this export is at least partially mediated by the CRM1 pathway (see above), the similar localization of wild-type Atx3 and the R282T mutant might be due to the presence of competitive nuclear export signals."
ATXN3 binds.
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"To establish if this decrease was specific for spinocerebellar ataxia type 3 and associated with the function of ataxin-3, we investigated the levels of both Usp15 mRNA and protein in a mouse model of another polyglutamine disorder, Huntington’s disease (Schilling et al. , xref )."
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"Genes that were part of this signature on the brain side were the TCF4, ATN1, PPP2R2B, ATXN10 and ATXN3, which are associated with neurodegenerative and developmental disorders such as Pitt-Hopkins Syndrome [XREF_BIBR], Dentatorubral pallidoluysian atrophy [XREF_BIBR], SCA12 [XREF_BIBR], SCA10 [XREF_BIBR] and SCA3 [XREF_BIBR]."
sparser
"Notably, the SCA3 pathogenic form of ataxin-3 (ataxin-3(exp)) impairs the misfolded protein clearance via mechanisms that are either dependent or independent of its deubiquitinase (DUB) activity, resulting in the accumulation of misfolded proteins and the progressive loss of neurons in SCA3."
L-glutamine affects ATXN3
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L-glutamine activates ATXN3.
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L-glutamine binds ATXN3.
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L-glutamine binds ATXN3. 2 / 2
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"VCP also has many associations with neurodegenerative disease as a component of intranuclear and cytoplasmic aggregates ( xref ), as the mutated gene in the rare neurological disorder inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia ( xref ), and through binding to Atx-3 and other polyglutamine proteins ( xref ; xref )."
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"In support of our idea that S345 phosphorylation is involved in regulating the interaction between ATX3 and Chk1 after persistent replication stress, the decreased association between ATX3 and Chk1 under replicative stress was restrained when Chk1 S345 phosphorylation was inhibited by CGK733, an inhibitor of ATM and ATR."
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"A case in this regard is a recent study which showed that the polyQ domain of wild-type ataxin 3 enables it to interact with beclin 1, a key initiator of autophagy, allowing the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome mediated degradation and thereby enabling autophagy."
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"At the 24-h time point, coexpression of normal Atx2 with pathogenic Atx3 caused the early appearance of SDS-insoluble Atx3 complexes that remain within the stacking gel (compare lanes 1 and 2), presumably reflecting protein accumulations that correlate with the early appearance of nuclear inclusions in cryosections."
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"XREF_BIBR SCA1, SCA2, Machado-Joseph or SCA3, SCA6, SCA7, SCA12, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA) are caused by (CAG) n repeat expansions in the ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, PPP2R2B, TBP, and ATN1 genes, respectively, and all lead to the expansion of a polyglutamine tract in the corresponding proteins."
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"On the other hand, the ratio of LC3-II and LC3-I and LC3 total levels (XREF_FIG, D) are enhanced in MJD fibroblasts overexpressing beclin-1, particularly in the presence of chloroquine, reaching similar levels as CTRL fibroblasts (XREF_FIG), which indicates that although the number of autophagosomes is decreased, the autophagic flux can be restored."
HSJ1a affects ATXN3
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HSJ1a activates ATXN3.
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HSJ1a inhibits ATXN3.
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HSJ1a increases the amount of ATXN3.
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HSJ1a binds ATXN3.
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HSJ1a decreases the amount of ATXN3.
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sparser
"Familial IGHD, however, is associated with at least four Mendelian disorders ( xref , xref , xref , xref , xref , xref , xref ), including two forms that have autosomal recessive inheritance (IGHD type IA, IB) as well as autosomal dominant (IGHD type II) and X−linked (IGHD III) forms. xref depicts the mutational spectrum of GHD, which is discussed in greater detail later in the review."
sparser
"Of these, 3 genes were unlikely to be involved in tooth agenesis: PLAC4 is mainly involved in placenta tissue formation ( xref ); CHST8 has been associated with autosomal recessive peeling skin syndrome ( xref ); SYNGAP1 is responsible for non-syndromic mental retardation autosomal dominant form 5 (OMIM 612621) ( xref ), a phenotype not reported in this family."
sparser
"The list of the diseases associated with OPLL includes hypophosphatemic rickets/osteomalacia, including an autosomal dominant form (MIM 193100) caused by FGF23 mutations, an X-linked dominant form (MIM 307800) caused by PHEX mutations, an X-linked recessive form (MIM 300554) caused by CLCN5 mutations, and autosomal recessive forms caused by DMP1 (MIM 600980) and ENPP1 (MIM 173335) mutations."
sparser
"Several forms of hypophosphatemic rickets are known, including an X-linked form (MIM 307800) caused by phosphate regulating endopeptidase homolog, X-linked ( PHEX ) mutations (MIM 300550), an autosomal dominant form (MIM 193100) caused by fibroblast growth factor 23 ( FGF23 ) mutations (MIM 605380), an X-linked recessive form (MIM 300554) caused by chloride channel, voltage-sensitive 5 ( CLCN5 ) mutations (MIM 300008), and autosomal recessive forms caused by dentin matrix acidic phosphoprotein 1 ( DMP1 ) (MIM 600980), hypophosphatemic rickets, autosomal recessive 2 ( ARHR2 ) (MIM 613312) or ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) (MIM 173335) mutations. 'tiptoe walking' ( TTW ) mouse, which has a spontaneous nonsense mutation in ENPP1 is a good model for OPLL.[ xref ] Also, OPPL is a frequent complication in patients with endocrine disorders including hypoparathyroidism[ xref ] and acromegaly/gigantism.[ xref ] However, most cases of OPLL are idiopathic."
sparser
"This study includes the following findings: (1) p62 directly associates with ataxin-3-Q80, and co-localizes with ataxin-3-Q80 aggresomes ( xref and xref ); (2) p62 regulates ataxin-3-Q80 aggresome formation without affecting the protein level and self-aggregation of ataxin-3-Q80 ( xref , xref and xref ); (3) The regulation of ataxin-3-Q80 aggresome formation by p62 has a protective role against ataxin-3-Q80 triggered cell toxicity ( xref )."
RAD23 family affects ATXN3
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ATXN3 binds RAD23 family. 10 / 19
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"The ataxin-3-Rad23 interaction also stabilizes the SCA3 protein by decelerating its proteasomal turnover; this process leads to higher levels of pathogenic ataxin-3 in Drosophila , but the higher levels are seemingly negated by the auto-protective role of ataxin-3 ( xref ; xref ). (Our ongoing, unpublished work indicates that Ubs1 also plays a protective role, potentially through mechanisms that involve pathogenic ataxin-3 binding certain ubiquitin species but not being able to process them)."
VCP binds ATXN3 and RAD23 family. 3 / 3
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"An autosomal dominant form of ALS and FTD linked to chromosome 9p 13–22 ( xref ) related to GGGGCC hexanucleotide repeat expansion in intron 1 of the C9orf72 gene has recently been identified as the most common pathologic mutation in familial and sporadic ALS/FTD as well as in familial ALS and familial FTD ( xref , xref )."
sparser
"We have explored methods to maximize the amount of genetic information that can be derived from a small family with an autosomal dominant form of ALS and show that analysis of high density SNP haplotypes are able to precisely define nearly all regions of the genome that are shared among the affected individuals."
sparser
"Further supporting a role for ER morphogenesis in neurologic disorders, the vesicle-associated membrane-protein associated protein B (VAP-B) mutant P56S that underlies a autosomal dominant form of familial ALS is associated with the production of a novel form of organized SER ( xref )."
sparser
"PNKP has been shown to promote transcription-coupled double-strand break repair ( xref ) and often performs transcription-coupled repair when in complex with huntingtin protein, RNA polymerase II subunit A, ataxin-3, and cyclic AMP-response element binding protein (CBP) ( xref )."
sparser
"The mechanisms for this were recently suggested to be through direct interactions between HTT and RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP) [ xref ], as well as complexes with the DNA double-strand break repair complex Ku70/Ku80 [ xref ]."
ATXN3 affects RAD23 family
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ATXN3 binds RAD23 family. 10 / 19
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sparser
"The ataxin-3-Rad23 interaction also stabilizes the SCA3 protein by decelerating its proteasomal turnover; this process leads to higher levels of pathogenic ataxin-3 in Drosophila , but the higher levels are seemingly negated by the auto-protective role of ataxin-3 ( xref ; xref ). (Our ongoing, unpublished work indicates that Ubs1 also plays a protective role, potentially through mechanisms that involve pathogenic ataxin-3 binding certain ubiquitin species but not being able to process them)."
VCP binds ATXN3 and RAD23 family. 3 / 3
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"An autosomal dominant form of ALS and FTD linked to chromosome 9p 13–22 ( xref ) related to GGGGCC hexanucleotide repeat expansion in intron 1 of the C9orf72 gene has recently been identified as the most common pathologic mutation in familial and sporadic ALS/FTD as well as in familial ALS and familial FTD ( xref , xref )."
sparser
"We have explored methods to maximize the amount of genetic information that can be derived from a small family with an autosomal dominant form of ALS and show that analysis of high density SNP haplotypes are able to precisely define nearly all regions of the genome that are shared among the affected individuals."
sparser
"Further supporting a role for ER morphogenesis in neurologic disorders, the vesicle-associated membrane-protein associated protein B (VAP-B) mutant P56S that underlies a autosomal dominant form of familial ALS is associated with the production of a novel form of organized SER ( xref )."
sparser
"This study includes the following findings: (1) p62 directly associates with ataxin-3-Q80, and co-localizes with ataxin-3-Q80 aggresomes ( xref and xref ); (2) p62 regulates ataxin-3-Q80 aggresome formation without affecting the protein level and self-aggregation of ataxin-3-Q80 ( xref , xref and xref ); (3) The regulation of ataxin-3-Q80 aggresome formation by p62 has a protective role against ataxin-3-Q80 triggered cell toxicity ( xref )."
RP affects ATXN3
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"In this RP cohort, symptoms were first reported at 5 years of age, thus confirming the earlier onset of RPGR -RP, particularly compared to autosomal dominant RP forms. xref , xref About 80% of patients presented variable degrees of myopia, and approximately one third of the cohort had high myopia, in line with previous observations in X-linked RP xref , xref and in RPGR -related RP. xref Our data confirm a faster BCVA decline in patients with high myopia as opposed to those without high myopia. xref Moreover, the patients with typical RP and high myopia had a significantly faster progression of the disease compared to those with sine pigmento RP in the absence of high myopia."
Proteasome affects ATXN3
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Proteasome binds ATXN3.
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Proteasome inhibits ATXN3.
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Proteasome inhibits ATXN3. 8 / 8
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"The neuroprotective role of HSJ1 has been demonstrated in different disease models : it suppresses the aggregation of polyglutamine expanded proteins, significantly enhancing mutant huntingtin solubility in Huntington disease in cells and in mice, and promoting misfolded protein targeting to the ubiquitin-proteasome system; HSJ1a cooperates with Hsp70 to promote proteasome degradation of ataxin-3, a protein responsible for spinocerebellar ataxia type 3 (SCA3); HSJ1a prevented the aggregation of the misfolded C289G Parkin, a Parkinson disease associated ubiquitin protein ligase mutant, and restored its function in mitophagy."
ATXN3 affects RP
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"In this RP cohort, symptoms were first reported at 5 years of age, thus confirming the earlier onset of RPGR -RP, particularly compared to autosomal dominant RP forms. xref , xref About 80% of patients presented variable degrees of myopia, and approximately one third of the cohort had high myopia, in line with previous observations in X-linked RP xref , xref and in RPGR -related RP. xref Our data confirm a faster BCVA decline in patients with high myopia as opposed to those without high myopia. xref Moreover, the patients with typical RP and high myopia had a significantly faster progression of the disease compared to those with sine pigmento RP in the absence of high myopia."
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"Further, it was shown that both normal and expanded ataxin 3 physiologically interact with HDAC3 and NCoR in a SCA3 cell model and in human pons tissue; however, normal ataxin 3 containing protein complexes showed increased histone deacetylase activity, whereas polyglutamine expanded ataxin 3 containing complexes had reduced deacetylase activity in target chromatin regions [XREF_BIBR]."
sparser
"Further, it was shown that both normal and expanded ataxin 3 physiologically interact with HDAC3 and NCoR in a SCA3 cell model and in human pons tissue; however, normal ataxin 3-containing protein complexes showed increased histone deacetylase activity, whereas polyglutamine-expanded ataxin 3-containing complexes had reduced deacetylase activity in target chromatin regions [ xref ]."
sparser
"A complete genetic ataxia panel, which included autosomal dominant ataxias caused by mutations in the genes associated with SCA 1, 2, 3, 5, 6, 7, 8, 10, 12, 13, 14, 17, 28 and DRPLA, and autosomal recessive ataxias caused by mutations in genes associated with SIL1, TTPA, FRDA, POLG, APTX, and SETX was negative."
sparser
"Optical coherence tomography (OCT) has been used as a non-invasive and easily applicable tool to evaluate structural changes of the retina and optic nerve in a wide spectrum of neurodegenerative diseases including the most common trinucleotide expansion SCAs, particularly in SCA-ATXN1 [ xref ], SCA-ATXN3 [ xref ], SCA-ATXN7 [ xref ], or a mixed SCA cohort (SCA-ATXN1,2,3 or SCA-CACNA1A) [ xref ]."
sparser
"Though the exact mechanism of this process is not entirely known, PCSK9 inhibitors can prevent PCSK9 from degrading the LDL-Rs and significantly increase the expression of LDL-Rs, which further reduces the levels of LDL-C in the plasma. xref Mutations of PCSK9 have been reported to significantly impact cardiovascular outcomes. xref The development of gain-of-function mutations in PCSK9 is associated with autosomal dominant hypercholesterolemia, while loss-of-function mutations are thought to correlate with lower LDL-C and reduced coronary heart disease without additional deleterious effects. xref "
sparser
"Gain-of-function mutations in PCSK9 are associated with autosomal dominant hypercholesterolemia ( xref , xref ); conversely, loss-of-function mutations in PCSK9 are associated with lowered levels of plasma LDL-C and decreased incidence of cardiovascular heart disease ( xref , xref )."
Low-density lipoprotein binds PCSK9 and ATXN3. 2 / 2
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sparser
"Mutations in and alterations in expression levels of alpha-synuclein cause autosomal dominant early onset heredity forms of Parkinson's disease, and sporadic Parkinson's disease is defined in part by the presence of Lewy bodies and Lewy neurites that are composed primarily of alpha-synuclein deposited in an aggregated amyloid fibril state."
sparser
"Wild-type lamin permits promoter release following tissue-specific activation, while a disease-linked point mutation in lamin impairs muscle-specific reorganization of a heterochromatic array during tissue-specific promoter activation in a dominant manner, which phenocopies the autosomal dominant form of EDMD [ xref ]."
sparser
"Following are some of such diseases: autosomal dominant form of EDMD (EDMD2, AD-EDMD; OMIM 181350) [ xref ] autosomal recessive EDMD (EDMD3, AR-EDMD; OMIM 604929), cardiomyopathy dilated 1A (CMD1A; OMIM 115200) [ xref ], limb-girdle muscular dystrophy type 1B (LGMD1B; OMIM 159001) [ xref ] congenital-type muscular dystrophy (OMIM 613205) [ xref ] and “heart-hand” syndrome (HHS; OMIM 610140) [ xref ] All mentioned diseases are caused by the mutations in LMNA gene, and have different clinical phenotypes."
sparser
"Mutations in and alterations in expression levels of alpha-synuclein cause autosomal dominant early onset heredity forms of Parkinson's disease, and sporadic Parkinson's disease is defined in part by the presence of Lewy bodies and Lewy neurites that are composed primarily of alpha-synuclein deposited in an aggregated amyloid fibril state."
ATXN3 affects L-glutamine
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ATXN3 activates L-glutamine.
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ATXN3 activates L-glutamine. 8 / 8
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"We have previously shown that rapamycin attenuates the phenotype in a mouse model of Huntington disease when administered pre-symptomatically and have recently extended this to demonstrate the effectiveness of rapamycin in a transgenic mouse model of spinocerebellar ataxia type 3, a polyglutamine disorder caused by mutations in the ataxin-3 gene."
reach
"Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is a polyglutamine (polyQ) neurodegenerative disorder caused by abnormal (more than 40 repeats) CAG nucleotide repeat expansions in the ataxin-3 (ATXN3) gene, which encodes a protein that is involved in ubiquitin-proteasome system degradation of proteins [XREF_BIBR, XREF_BIBR]."
| PMC
ATXN3 inhibits L-glutamine.
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7
ATXN3 binds L-glutamine.
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L-glutamine binds ATXN3. 2 / 2
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sparser
"VCP also has many associations with neurodegenerative disease as a component of intranuclear and cytoplasmic aggregates ( xref ), as the mutated gene in the rare neurological disorder inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia ( xref ), and through binding to Atx-3 and other polyglutamine proteins ( xref ; xref )."
sparser
"Wild-type lamin permits promoter release following tissue-specific activation, while a disease-linked point mutation in lamin impairs muscle-specific reorganization of a heterochromatic array during tissue-specific promoter activation in a dominant manner, which phenocopies the autosomal dominant form of EDMD [ xref ]."
sparser
"Following are some of such diseases: autosomal dominant form of EDMD (EDMD2, AD-EDMD; OMIM 181350) [ xref ] autosomal recessive EDMD (EDMD3, AR-EDMD; OMIM 604929), cardiomyopathy dilated 1A (CMD1A; OMIM 115200) [ xref ], limb-girdle muscular dystrophy type 1B (LGMD1B; OMIM 159001) [ xref ] congenital-type muscular dystrophy (OMIM 613205) [ xref ] and “heart-hand” syndrome (HHS; OMIM 610140) [ xref ] All mentioned diseases are caused by the mutations in LMNA gene, and have different clinical phenotypes."
reach
"Further, it was shown that both normal and expanded ataxin 3 physiologically interact with HDAC3 and NCoR in a SCA3 cell model and in human pons tissue; however, normal ataxin 3 containing protein complexes showed increased histone deacetylase activity, whereas polyglutamine expanded ataxin 3 containing complexes had reduced deacetylase activity in target chromatin regions [XREF_BIBR]."
sparser
"Further, it was shown that both normal and expanded ataxin 3 physiologically interact with HDAC3 and NCoR in a SCA3 cell model and in human pons tissue; however, normal ataxin 3-containing protein complexes showed increased histone deacetylase activity, whereas polyglutamine-expanded ataxin 3-containing complexes had reduced deacetylase activity in target chromatin regions [ xref ]."
reach
"No change in the number of LC3-II vesicles was observed when the Q35 tract was expressed in beclin 1 depleted cells (XREF_FIG) and the inhibitory effect of Q35 on beclin 1 levels and autophagy in beclin 1 expressing cells was rescued by ataxin-3 overexpression (XREF_FIG), compatible with the model that the Q35 acts by impairing ataxin-3 control of beclin 1 levels."
ATXN3 affects apoptotic process
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ATXN3 activates apoptotic process.
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12
ATXN3 inhibits apoptotic process.
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ATXN3 inhibits apoptotic process. 2 / 2
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"ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription and expression of p53 target genes and promotes p53 dependent apoptosis in both mammalian cells and the central nervous system of zebrafish."
sparser
"A complete genetic ataxia panel, which included autosomal dominant ataxias caused by mutations in the genes associated with SCA 1, 2, 3, 5, 6, 7, 8, 10, 12, 13, 14, 17, 28 and DRPLA, and autosomal recessive ataxias caused by mutations in genes associated with SIL1, TTPA, FRDA, POLG, APTX, and SETX was negative."
sparser
"Optical coherence tomography (OCT) has been used as a non-invasive and easily applicable tool to evaluate structural changes of the retina and optic nerve in a wide spectrum of neurodegenerative diseases including the most common trinucleotide expansion SCAs, particularly in SCA-ATXN1 [ xref ], SCA-ATXN3 [ xref ], SCA-ATXN7 [ xref ], or a mixed SCA cohort (SCA-ATXN1,2,3 or SCA-CACNA1A) [ xref ]."
sparser
"In contrast, familial cases of AD represent less than 2 percent of all presentations ( xref ), usually occur prior to age 55 ( xref ), and represent an autosomal dominant form of a mutated amyloid precursor protein (APP) gene as well as mutations in the presenilin 1 or 2 genes ( xref )."
APP binds ATXN3 and Alzheimer Disease. 2 / 2
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2
ATXN3 affects AD
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16
sparser
"Indeed, some, but not all, investigators have considered a PSEN1 mutation in Auguste Deter, Alzheimer’s original patient. xref In actuality, the vast majority of patients with early-onset AD have a nonfamilial, or sporadic, form. xref Only approximately 11% of those with early-onset AD (about 0.6% of the total of all patients with AD, including the late-onset form) have familial AD associated with one of the three known autosomal dominant mutations: amyloid precursor protein ( APP ), presenilin 1 ( PSEN1 ), or presenilin 2 ( PSEN2 ). xref Studies screening for these genes in patients with early-onset AD report a prevalence of 0.8% for APP, 1.1% for PSEN1, and as high as 13% for potential pathogenic variants of PSEN2, which can present even after age 65. xref – xref These forms of familial AD are usually inherited from a parent with a similar age of onset of early-onset AD, generally in the forties or fifties (having a positive family history of late-onset AD has no effect). xref These three pathogenic mutations, which lead to aberrant cleavage or aggregation of the amyloid precursor protein, result in the more typical amnestic AD but can have diagnostic features such as spastic paraparesis, early myoclonus, seizures, dysarthria, pseudobulbar affect, more extensive amyloid angiopathy, and atypical amyloid plaque morphology and distribution. xref Some PSEN1 mutations (such as A79V) can be variable and sometimes mild, with ages of onset ranging from 53 to 84. xref "
sparser
"Patients with an autosomal dominant familial form of early-onset AD not only have an increased risk for the development of AD among relatives, but may also have atypical clinical features, including headaches, myoclonus, seizures, gait abnormalities, pseudobulbar palsy, or hyperreflexia. xref , xref Second, overall deterioration is faster in early-onset AD as compared to late-onset AD (not related to APOE ). xref Several studies indicate that patients with early-onset AD have a potentially more aggressive clinical course. xref – xref After controlling for the direct effects of aging on mortality, patients with early-onset AD are at a greater risk for mortality compared to those with late-onset AD, xref and early-onset AD accounts for a large number of premature deaths among those 40 to 64 years of age. xref Third, patients with early-onset AD have a longer duration of the disease before diagnosis (about 1.6 years), xref , xref probably reflecting missed or delayed diagnosis or a greater extent of evaluation for diagnosis. xref Fourth, patients with early-onset AD are more likely to have a history of traumatic brain injury as a risk factor for dementia. xref However, patients with early-onset AD have decreased cerebrovascular risk factors, circulatory problems, diabetes mellitus, and obesity than those with late-onset AD. xref , xref , xref "
sparser
"In contrast, familial cases of AD represent less than 2 percent of all presentations ( xref ), usually occur prior to age 55 ( xref ), and represent an autosomal dominant form of a mutated amyloid precursor protein (APP) gene as well as mutations in the presenilin 1 or 2 genes ( xref )."
APP binds ATXN3 and Alzheimer Disease. 2 / 2
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2
AD affects ATXN3
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16
sparser
"Indeed, some, but not all, investigators have considered a PSEN1 mutation in Auguste Deter, Alzheimer’s original patient. xref In actuality, the vast majority of patients with early-onset AD have a nonfamilial, or sporadic, form. xref Only approximately 11% of those with early-onset AD (about 0.6% of the total of all patients with AD, including the late-onset form) have familial AD associated with one of the three known autosomal dominant mutations: amyloid precursor protein ( APP ), presenilin 1 ( PSEN1 ), or presenilin 2 ( PSEN2 ). xref Studies screening for these genes in patients with early-onset AD report a prevalence of 0.8% for APP, 1.1% for PSEN1, and as high as 13% for potential pathogenic variants of PSEN2, which can present even after age 65. xref – xref These forms of familial AD are usually inherited from a parent with a similar age of onset of early-onset AD, generally in the forties or fifties (having a positive family history of late-onset AD has no effect). xref These three pathogenic mutations, which lead to aberrant cleavage or aggregation of the amyloid precursor protein, result in the more typical amnestic AD but can have diagnostic features such as spastic paraparesis, early myoclonus, seizures, dysarthria, pseudobulbar affect, more extensive amyloid angiopathy, and atypical amyloid plaque morphology and distribution. xref Some PSEN1 mutations (such as A79V) can be variable and sometimes mild, with ages of onset ranging from 53 to 84. xref "
sparser
"Patients with an autosomal dominant familial form of early-onset AD not only have an increased risk for the development of AD among relatives, but may also have atypical clinical features, including headaches, myoclonus, seizures, gait abnormalities, pseudobulbar palsy, or hyperreflexia. xref , xref Second, overall deterioration is faster in early-onset AD as compared to late-onset AD (not related to APOE ). xref Several studies indicate that patients with early-onset AD have a potentially more aggressive clinical course. xref – xref After controlling for the direct effects of aging on mortality, patients with early-onset AD are at a greater risk for mortality compared to those with late-onset AD, xref and early-onset AD accounts for a large number of premature deaths among those 40 to 64 years of age. xref Third, patients with early-onset AD have a longer duration of the disease before diagnosis (about 1.6 years), xref , xref probably reflecting missed or delayed diagnosis or a greater extent of evaluation for diagnosis. xref Fourth, patients with early-onset AD are more likely to have a history of traumatic brain injury as a risk factor for dementia. xref However, patients with early-onset AD have decreased cerebrovascular risk factors, circulatory problems, diabetes mellitus, and obesity than those with late-onset AD. xref , xref , xref "
Heat Shock Protein affects ATXN3
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15
reach
"Our results reveal a mechanism to explain how the p97–ATX3–RNF8 complex fine‐tunes DSB repair by preventing excessive RNF8‐dependent K63‐Ub modifications and 5′‐DNA end resection and consequently promoting the NHEJ pathway, an essential pathway for cell survival after IR and thus cancer cell resistance to radiotherapy (Jeggo et al, 2011; Jeggo & Lobrich, 2015)."
reach
"However, further studies are required to address this important question in the context of the p97–ATX3–RNF8 complex and chromatin dynamics after DSB formation.While our manuscript was in preparation, Pfeiffer et al (2017) reported that ATX3 is a DUB acting at DSB sites and removes ubiquitinated chains from MDC1 to prevent a premature removal of MDC1 from the breaks."
ATXN3 affects Proteasome
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2
ATXN3 binds Proteasome.
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2
ATXN3 activates Proteasome.
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ATXN3 activates Proteasome. 1 / 3
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"Whether CHIP is the primary mediator of ubiquitin dependent degradation of ataxin-3 is controversial : XREF_BIBR reported that CHIP ubiquitinates ataxin-3 and directs it to the proteasome for degradation, whereas XREF_BIBR reported that another ubiquitin ligase, E4B, mediates ataxin-3 degradation while CHIP has no effect."
ATXN3 affects transcription, DNA-templated
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ATXN3 inhibits transcription, DNA-templated.
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ATXN3 inhibits transcription, DNA-templated. 10 / 10
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1
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"ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription and expression of p53 target genes and promotes p53 dependent apoptosis in both mammalian cells and the central nervous system of zebrafish."
reach
"In the present study we use cell transfections, in vitro binding, co-immunoprecipitations, and reporter assays to show that the polyglutamine disease protein, ataxin-3, interacts with the major histone acetyltransferases cAMP-response-element binding protein (CREB)-binding protein, p300, and p300 and CREB binding protein associated factor and inhibits transcription by these coactivators."
ATXN3 activates transcription, DNA-templated.
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3
sparser
"PNKP has been shown to promote transcription-coupled double-strand break repair ( xref ) and often performs transcription-coupled repair when in complex with huntingtin protein, RNA polymerase II subunit A, ataxin-3, and cyclic AMP-response element binding protein (CBP) ( xref )."
sparser
"The mechanisms for this were recently suggested to be through direct interactions between HTT and RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP) [ xref ], as well as complexes with the DNA double-strand break repair complex Ku70/Ku80 [ xref ]."
sparser
"Various loss-of-function mutations in KAL1 , encoding the extracellular matrix glycoprotein anosmin-1, and in FGFR1 or FGF8 , encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, underlie the X-chromosome linked form and an autosomal dominant form of KS, respectively."
sparser
"Collectively, our results suggest a novel mechanism of ataxin-3-mediated HDAC6-dependent aggresome formation, where the aggregate-specific deubiquitinase, ataxin-3, cleaves (poly)ubiquitin moieties in polyubiquitinated proteins to expose their C-terminal diglycine motifs, providing a handle for HDAC6 binding and subsequent transport to the aggresome."
E3_Ub_ligase affects ATXN3
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E3_Ub_ligase binds ATXN3.
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E3_Ub_ligase binds ATXN3. 7 / 7
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sparser
"The regulation of ataxin-3 activity through ubiquitination might depend on the interaction of ataxin-3 with several E3 ubiquitin ligases (Durcan and Fon, xref ), such as the C-terminus of 70 kDa heat-shock protein (Hsp70)-interacting protein (CHIP), parkin, and E4B (Figure xref ), since all were shown to promote ataxin-3 ubiquitination and regulate its degradation by the proteasome (Matsumoto et al., xref ; Jana et al., xref ; Miller et al., xref )."
E3_Ub_ligase ubiquitinates ATXN3.
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4
1
reach
"Phosphorylations of ATX3 by protein casein kinase 2 (CK2) stimulate SCA3 pathogenesis by altering its stability, nuclear localization, and inclusion formation [50,51], while GSK3β-mediated phosphorylation inhibits ATX3 aggregation which has a protective role in SCA3 pathophysiology [94]."
sparser
"Phosphorylations of ATX3 by protein casein kinase 2 (CK2) stimulate SCA3 pathogenesis by altering its stability, nuclear localization, and inclusion formation [ xref , xref ], while GSK3β-mediated phosphorylation inhibits ATX3 aggregation which has a protective role in SCA3 pathophysiology [ xref ]."
BP affects ATXN3
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12
sparser
"Various loss-of-function mutations in KAL1 , encoding the extracellular matrix glycoprotein anosmin-1, and in FGFR1 or FGF8 , encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, underlie the X-chromosome linked form and an autosomal dominant form of KS, respectively."
sparser
"Collectively, our results suggest a novel mechanism of ataxin-3-mediated HDAC6-dependent aggresome formation, where the aggregate-specific deubiquitinase, ataxin-3, cleaves (poly)ubiquitin moieties in polyubiquitinated proteins to expose their C-terminal diglycine motifs, providing a handle for HDAC6 binding and subsequent transport to the aggresome."
ATXN3 affects DNA damage checkpoint
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ATXN3 activates DNA damage checkpoint.
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Mutated ATXN3 activates DNA damage checkpoint. 10 / 10
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"Either overexpression of PNKP or pharmacological inhibition of ATM in mutant ATXN3 expressing cells blocked aberrant activation of the pro death pathways and reduced cell death, suggesting that mutant ATXN3 mediated chronic activation of the DNA damage response ATM signaling pathway plays a pivotal role in neuronal dysfunction and neurodegeneration in SCA3."
reach
"Consistent with our hypothesis, ATXN3-Q84 expression failed to stimulate phosphorylation of Chk2 and p53 in the presence of the ATM inhibitor Ku55933 (XREF_SUPPLEMENTARY), substantiating our interpretation that mutant ATXN3 stimulates the DNA damage response p53 pathway via activating ATM."
ATXN3 inhibits DNA damage checkpoint.
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2
ATXN3 affects BP
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12
reach
"Our data suggest that in addition to activating the DNA damage induced p53 pathway as described earlier in SCA3 [XREF_BIBR, XREF_BIBR], mutant ATXN3 also activates the ATM dependent cAbl --> PKCdelta pro apoptotic pathway in parallel to cause neuronal dysfunction and eventually facilitating systemic neuronal degeneration in SCA3 brain (XREF_FIG)."
reach
"Our accompanying manuscript clearly shows that either PNKP depletion or the expression of mutant ATXN3 leads to ATM mediated activation of two parallel proapoptotic pathways; one is p53- and the other c-Abl --> PKCdelta mediated apoptotic cell death, a hallmark of neuropathogenesis (Gao et al.."
PKD affects ATXN3
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11
sparser
"Fedeles et al. used mouse mutants to show that the main proteins implicated in ADPKD, autosomal recessive PKD and autosomal dominant polycystic liver disease functionally interact. xref Loss of glucosidase 2 subunit β or SEC63 reduces polycystin-1 and, to a lesser extent, polycystin-2 expression, blocks polycystin-1 trafficking to primary cilia, causes renal and hepatic cysts, worsens cystic disease in heterozygous Pkd1 +/− and Pkd2 +/− mice and induces renal cystogenesis inPkhd1 del4/del4 mice."
ATXN3 affects PKD
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11
sparser
"Fedeles et al. used mouse mutants to show that the main proteins implicated in ADPKD, autosomal recessive PKD and autosomal dominant polycystic liver disease functionally interact. xref Loss of glucosidase 2 subunit β or SEC63 reduces polycystin-1 and, to a lesser extent, polycystin-2 expression, blocks polycystin-1 trafficking to primary cilia, causes renal and hepatic cysts, worsens cystic disease in heterozygous Pkd1 +/− and Pkd2 +/− mice and induces renal cystogenesis inPkhd1 del4/del4 mice."
PQE proteins affects ATXN3
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10
sparser
"That is the isoform where the other two SD mutations were identified – the A95T mutation, a potential candidate mutation for Sézary syndrome (SS; MIM #254400), a leukemic variant cutaneous T-cell lymphoma, and the R36C mutation, identified as the cause of an autosomal dominant form of SCA29 in a mother ( de novo ) and her children (inherited) ( xref , xref )."
ATXN3 affects Machado-Joseph Disease
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sparser
"That is the isoform where the other two SD mutations were identified – the A95T mutation, a potential candidate mutation for Sézary syndrome (SS; MIM #254400), a leukemic variant cutaneous T-cell lymphoma, and the R36C mutation, identified as the cause of an autosomal dominant form of SCA29 in a mother ( de novo ) and her children (inherited) ( xref , xref )."
reach
"Interestingly, mutation in the VBM motif of Atx3 100Q (Atx3 100Q / VBM *, 282 RKRR to HNHH), which disrupts the specific interaction between Atx3 and P97, significantly abolished the sequestration of P97 into aggregates; even the amount of P97 sequestered by the mutant was less than that by Atx3 22Q under the condition of similar amounts of the Atx3 aggregates (XREF_FIG)."
Valproic acid affects ATXN3
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Valproic acid decreases the amount of ATXN3.
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Valproic acid decreases the amount of ATXN3. 6 / 6
6
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Valproic acid inhibits ATXN3.
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3
USP19_b affects ATXN3
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9
USP19_b increases the amount of ATXN3.
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5
reach
"Although USP19_b also up-regulates the protein levels of endogenous Atx3, and overexpressed Atx3 22Q and Htt-N552 18Q, we have not observed the aggregates or inclusions formed by overexpressed proteins with normal polyQ lengths (Atx3 22Q, Htt-N552 18Q) in the cultured cells, even in the presence of overexpressed USP19_b (XREF_FIG)."
USP19_b activates ATXN3.
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4
sparser
"Two disease entities have been identified: an autosomal dominant form caused by a STAT3 gene mutation (OMIM#102582) [ xref ] and an autosomal recessive form primarily caused by a loss-of-function mutation in the dedicator of cytokinesis 8 (DOCK8) gene (OMIM#611432) [ xref , xref ]."
sparser
"First reported in 2009, DOCK8 deficiency was identified as the underlying abnormality in the majority of patients with autosomal recessive Hyper IgE Syndrome (AR-HIES) [ xref , xref ]; the autosomal dominant form of this syndrome (AD-HIES) caused by signal transducer and activator of transcription 3 ( STAT3 ) mutations [ xref , xref ]."
sparser
"The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)-HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis."
sparser
"In fact, higher levels of Ub-Rheb were co-IPed with ATXN3 when N-Ethylmaleimide, a deubiquitinase inhibitor, was included in the lysis and purification buffers ( xref ), supporting the idea that the Ub-Rheb that binds to ATXN3 was subjected to deubiquitination during the isolation processes."
reach
"Ataxin-3 interacts with the major histone acetyltransferases cAMP-response-element binding protein (CREB)-binding protein (CBP), p300, and p300 and CREB binding protein associated factor (KAT2B and PCAF, Figures XREF_FIG and XREF_FIG), and is proposed to inhibit transcription in specific promoters (e.g., MMP-2 promoter) either by blocking access to histone acetylation sites or through recruitment of histone deacetylase 3 (HDAC3) and nuclear receptor co-repressor (NCOR1; Figures XREF_FIG and XREF_FIG)."
sparser
"Doubled-layered patella, a type of bipartite patella with a coronal septum that divides the patella into anterior and posterior segments, is recognized as a specific radiological feature of the recessive form of MED [Scheffield EG; 1998]; however, it was also seen in a patient with an autosomal dominant form caused by COL9A2 mutation [ xref ]."
sparser
"For the autosomal dominant forms of MED, the mutations exert their phenotypic effect through a dominant negative mechanism, leading to reduced secretion of structurally abnormal proteins into the extracellular matrix as well as intracellular retention of the abnormal proteins within the rough endoplasmic reticulum (RER) [ xref ; xref ; xref ; xref ; xref ]."
sparser
"Even if nicotinic acetylcholine receptor genes are traditionally associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), this single-family description can open new possibilities in the genetic diagnosis, molecular characterization, and management of CHRNA2-related epilepsy."
sparser
"Examples of hyperactive disorders include gain-of-function mutations in P/Q-type calcium channels, linked to familial hemiplegic migraine type 1 (Ophoff et al., xref ; Tottene et al., xref ), or mutations in neuronal nAChRs associated to autosomal dominant nocturnal frontal lobe epilepsy (Steinlein et al., xref ; Klaassen et al., xref )."
sparser
"Amino acid mutations in the human α4β2 nAChR associated with autosomal dominant nocturnal frontal lobe epilepsy, which when are engineered in the corresponding α4β2 nAChR in mice, lead to disturbances of inhibitory synchronization of cortical networks by GABAergic interneurons ( xref )."
sparser
"Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is
associated with genetically heterogeneous mutations in the neuronal nicotinic
acetylcholine receptor in several international kindreds. xref Video-EEG polysomnography is necessary for
definitive diagnosis, confirming abrupt awakening, and stereotypical motor behavior
with vocalization and violent or dystonic-dyskinetic movements."
sparser
"Two disease entities have been identified: an autosomal dominant form caused by a STAT3 gene mutation (OMIM#102582) [ xref ] and an autosomal recessive form primarily caused by a loss-of-function mutation in the dedicator of cytokinesis 8 (DOCK8) gene (OMIM#611432) [ xref , xref ]."
sparser
"First reported in 2009, DOCK8 deficiency was identified as the underlying abnormality in the majority of patients with autosomal recessive Hyper IgE Syndrome (AR-HIES) [ xref , xref ]; the autosomal dominant form of this syndrome (AD-HIES) caused by signal transducer and activator of transcription 3 ( STAT3 ) mutations [ xref , xref ]."
sparser
"The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)-HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis."
sparser
"In fact, higher levels of Ub-Rheb were co-IPed with ATXN3 when N-Ethylmaleimide, a deubiquitinase inhibitor, was included in the lysis and purification buffers ( xref ), supporting the idea that the Ub-Rheb that binds to ATXN3 was subjected to deubiquitination during the isolation processes."
ATXN3 affects DNA Damage
|
9
reach
"Ataxin-3 interacts with the major histone acetyltransferases cAMP-response-element binding protein (CREB)-binding protein (CBP), p300, and p300 and CREB binding protein associated factor (KAT2B and PCAF, Figures XREF_FIG and XREF_FIG), and is proposed to inhibit transcription in specific promoters (e.g., MMP-2 promoter) either by blocking access to histone acetylation sites or through recruitment of histone deacetylase 3 (HDAC3) and nuclear receptor co-repressor (NCOR1; Figures XREF_FIG and XREF_FIG)."
sparser
"Doubled-layered patella, a type of bipartite patella with a coronal septum that divides the patella into anterior and posterior segments, is recognized as a specific radiological feature of the recessive form of MED [Scheffield EG; 1998]; however, it was also seen in a patient with an autosomal dominant form caused by COL9A2 mutation [ xref ]."
sparser
"For the autosomal dominant forms of MED, the mutations exert their phenotypic effect through a dominant negative mechanism, leading to reduced secretion of structurally abnormal proteins into the extracellular matrix as well as intracellular retention of the abnormal proteins within the rough endoplasmic reticulum (RER) [ xref ; xref ; xref ; xref ; xref ]."
sparser
"Even if nicotinic acetylcholine receptor genes are traditionally associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), this single-family description can open new possibilities in the genetic diagnosis, molecular characterization, and management of CHRNA2-related epilepsy."
sparser
"Examples of hyperactive disorders include gain-of-function mutations in P/Q-type calcium channels, linked to familial hemiplegic migraine type 1 (Ophoff et al., xref ; Tottene et al., xref ), or mutations in neuronal nAChRs associated to autosomal dominant nocturnal frontal lobe epilepsy (Steinlein et al., xref ; Klaassen et al., xref )."
sparser
"Amino acid mutations in the human α4β2 nAChR associated with autosomal dominant nocturnal frontal lobe epilepsy, which when are engineered in the corresponding α4β2 nAChR in mice, lead to disturbances of inhibitory synchronization of cortical networks by GABAergic interneurons ( xref )."
sparser
"Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is
associated with genetically heterogeneous mutations in the neuronal nicotinic
acetylcholine receptor in several international kindreds. xref Video-EEG polysomnography is necessary for
definitive diagnosis, confirming abrupt awakening, and stereotypical motor behavior
with vocalization and violent or dystonic-dyskinetic movements."
ATXN3 affects AI
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Alpha,alpha-trehalose affects ATXN3
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Alpha,alpha-trehalose activates ATXN3.
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Alpha,alpha-trehalose activates ATXN3. 4 / 4
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4
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"Trehalose mediated improvements in motor behaviour were associated with a reduction of the MJD associated neuropathology, as MJD transgenic mice treated with trehalose presented preservation of cerebellar layers thickness and a decrease in the size of ataxin-3 aggregates in Purkinje cells."
reach
"Trehalose mediated improvements in motor behaviour were associated with a reduction of the MJD associated neuropathology, as MJD transgenic mice treated with trehalose presented preservation of cerebellar layers thickness and a decrease in the size of ataxin-3 aggregates in Purkinje cells."
reach
"XREF_FIG c a close to significant increase in the stride length (Control = 6.02 +/-0.12 cm, 2% trehalose = 6.51 +/-0.18 cm, p = 0.052, Student 's t test) and a significant decrease in the front base width (Control = 2.01 +/-0.08 cm, 2% trehalose = 1.77 +/-0.07 cm, p = 0.047; Student 's t test) was observed in MJD transgenic females treated with 2% trehalose, revealing that trehalose reduced the gait deficits of MJD transgenic females."
Alpha,alpha-trehalose inhibits ATXN3.
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2
Alpha,alpha-trehalose decreases the amount of ATXN3.
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2
Alpha,alpha-trehalose decreases the amount of mutated ATXN3. 2 / 2
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2
reach
"Our results reveal a mechanism to explain how the p97–ATX3–RNF8 complex fine‐tunes DSB repair by preventing excessive RNF8‐dependent K63‐Ub modifications and 5′‐DNA end resection and consequently promoting the NHEJ pathway, an essential pathway for cell survival after IR and thus cancer cell resistance to radiotherapy (Jeggo et al, 2011; Jeggo & Lobrich, 2015)."
reach
"However, further studies are required to address this important question in the context of the p97–ATX3–RNF8 complex and chromatin dynamics after DSB formation.While our manuscript was in preparation, Pfeiffer et al (2017) reported that ATX3 is a DUB acting at DSB sites and removes ubiquitinated chains from MDC1 to prevent a premature removal of MDC1 from the breaks."
ATXN3 affects Cell Survival
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4
ATXN3 inhibits Cell Survival.
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2
ATXN3 inhibits Cell Survival. 2 / 5
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2
reach
"Aggregation of expanded ataxin-3 in PC6-3 ataxin-3 (Q108) cells decreased cell survival only in the presence of high 3-NP concentrations, compared to HEK EGFP-ataxin-3 (Q84) cells or MJD cerebellar granule cells, which may account for a lower expression of the transgene in these cells."
ATXN3 activates Cell Survival.
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2
ATXN3 activates Cell Survival. 2 / 3
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2
reach
"Altogether, these results further support our findings that ATX3 selectively fine‐tunes DSB repair by preventing extensive RNF8/K63‐ubiquitin signalling, which balances DSB repair pathway choice.Finally, if this model is correct, then removal of RNF8 in ATX3‐depleted cells should prevent excessive 5′‐DNA end resection and restore cell survival after IR."
sparser
"Further, it was shown that both normal and expanded ataxin 3 physiologically interact with HDAC3 and NCoR in a SCA3 cell model and in human pons tissue; however, normal ataxin 3-containing protein complexes showed increased histone deacetylase activity, whereas polyglutamine-expanded ataxin 3-containing complexes had reduced deacetylase activity in target chromatin regions [ xref ]."
Migraine with Aura affects ATXN3
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7
reach
"ATXN3 transcript levels, although variable across experiments, were actually higher when FBXL3 was overexpressed, with or without knockdown of CUL1 (XREF_SUPPLEMENTARY), indicating that the observed FBXL3 mediated reduction of ATXN3 levels occurs at the protein rather than transcriptional level, as expected."
reach
"Over-expression of the Drosophila DNAJB1 homolog, dHDJ1, suppressed polyQ Htt- and ATXN3 dependent toxicity [XREF_BIBR, XREF_BIBR], and the effect of dHDJ1 on ATXN3 mediated toxicity was enhanced by over-expression with wildtype Hsp70 but inhibited by co-expression with a dominant negative mutant of Hsp70."
reach
"DNAJA1 effectively degrades huntington aggregates; DNAJB1 can degrade protein aggregates ataxin-3; DNAJB2 can inhibit the formation of huntington aggregates; DNAJB6 can inhibit the aggregation of Aβ 42 and α-synuclein; DNAJC5 can promote the release of TDP-43, τ protein, and α-synuclein into the extracellular space."
sparser
"Several different genes have been identified as susceptibility genes of familial PD(FDP)including alpha-synuclein gene (SNCA) and the leucine-rich repeat kinase 2 (LRRK2) mutations, which underlie autosomal dominant forms of PD, and mutations or multiplications of PINK1(PTEN-induced putative kinase 1), PARK7(Protein DJ1), and PARK2(Parkinson juvenile disease protein 2), with autosomal recessive forms of PD [ xref – xref ], especially in Chinese [ xref , xref ]."
reach
"XREF_BIBR SCA1, SCA2, Machado-Joseph or SCA3, SCA6, SCA7, SCA12, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA) are caused by (CAG) n repeat expansions in the ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, PPP2R2B, TBP, and ATN1 genes, respectively, and all lead to the expansion of a polyglutamine tract in the corresponding proteins."
sparser
"Further, it was shown that both normal and expanded ataxin 3 physiologically interact with HDAC3 and NCoR in a SCA3 cell model and in human pons tissue; however, normal ataxin 3-containing protein complexes showed increased histone deacetylase activity, whereas polyglutamine-expanded ataxin 3-containing complexes had reduced deacetylase activity in target chromatin regions [ xref ]."
ATXN3 affects Migraine with Aura
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7
ATXN3 affects E3_Ub_ligase
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7
E3_Ub_ligase binds ATXN3. 7 / 7
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7
sparser
"The regulation of ataxin-3 activity through ubiquitination might depend on the interaction of ataxin-3 with several E3 ubiquitin ligases (Durcan and Fon, xref ), such as the C-terminus of 70 kDa heat-shock protein (Hsp70)-interacting protein (CHIP), parkin, and E4B (Figure xref ), since all were shown to promote ataxin-3 ubiquitination and regulate its degradation by the proteasome (Matsumoto et al., xref ; Jana et al., xref ; Miller et al., xref )."
sparser
"Several different genes have been identified as susceptibility genes of familial PD(FDP)including alpha-synuclein gene (SNCA) and the leucine-rich repeat kinase 2 (LRRK2) mutations, which underlie autosomal dominant forms of PD, and mutations or multiplications of PINK1(PTEN-induced putative kinase 1), PARK7(Protein DJ1), and PARK2(Parkinson juvenile disease protein 2), with autosomal recessive forms of PD [ xref – xref ], especially in Chinese [ xref , xref ]."
reach
"XREF_BIBR SCA1, SCA2, Machado-Joseph or SCA3, SCA6, SCA7, SCA12, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA) are caused by (CAG) n repeat expansions in the ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, PPP2R2B, TBP, and ATN1 genes, respectively, and all lead to the expansion of a polyglutamine tract in the corresponding proteins."
Endoplasmic reticulum affects ATXN3
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2
4
Endoplasmic reticulum binds ATXN3.
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4
Endoplasmic reticulum binds ATXN3. 4 / 4
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4
sparser
"The simplest explanation of these observations is that a small fraction of atx3 is transiently associated with the ER membrane via interactions with p97 and VIMP. atx3 may shuttle on and off p97 to promote PAD, a process that is linked to the ATPase cycle of p97 and to the subsequent delivery of substrates to the proteasome."
Endoplasmic reticulum inhibits ATXN3.
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2
Endoplasmic reticulum inhibits ATXN3. 2 / 2
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2
Calcium(2+) affects ATXN3
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6
sparser
"For instance, SLC26A4, associated with autosomal recessive NSHL xref and Pendred syndrome, is a gene coding for pendrin, a chloride/iodide transporter; COCH, responsible for autosomal dominant non syndromic post-lingual with a progressive onset in adulthood xref , encodes for cochlin, a component of the extracellular matrix of the inner ear; POU3F4, responsible for an X-linked non syndromic progressive and profound sensorineural hearing loss xref , encodes for a transcription factor; while WFS1 associated with autosomal recessive Wolfram syndrome and autosomal dominant low frequency NSHL xref , xref , is a gene coding for the glycoprotein wolframin."
UBL affects ATXN3
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6
N-VCP affects ATXN3
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6
sparser
"Two substitution mutations in the cystathionine-β-synthase (CBS) subdomain of IMPDH1, which are associated with human autosomal dominant retinitis pigmentosa, impair nucleic acid binding but not enzymatic activity xref , suggesting that the inability of mutant IMPDH to bind to DNA contributes to human disease."
sparser
"Whilst it may be questioned whether the treatment with BLD-2736 may have instead decreased full-length ataxin-3 through effects on the expression of EGFP-ataxin-3 via an effect on transcription, we previously demonstrated that treatment with calpeptin decreased the presence of full length human ataxin-3 protein, without altering the levels of human ataxin-3 mRNA, and that this effect was prevented by cotreatment with the autophagy inhibitor, chloroquine [ xref ]."
| PMC
sparser
"Mutations to the dynamin 2 gene ( DNM2 ) were recently associated with the autosomal dominant form of CNM while X-linked CNMs were associated with mutations in DNM2 , AMPH (amphiphysin), MTM1 (myotubularin) and most recently MTMR14 (myotubularin-related protein-14) genes (Laporte et al., xref , xref ; Jungbluth et al., xref ; Romero, xref ; Romero and Bitoun, xref )."
sparser
"Autosomal dominant centronuclear myopathy is classically associated with mutations in DNM2 which codes for dynamin 2 [ xref ], a GTPase that is involved in the mechanisms of endocytosis and transport of organelles along the network of microtubules, and also plays a key role in centrosome formation [ xref ]."
ATXN3 affects polyQ
|
6
reach
"Additionally, ataxin-3 suppresses polyQ dependent degeneration without eliminating the polyQ species, based on western blots, suggesting that the elimination of the disease causing agent by the proteasome or through autophagy is not part of the protective aspect of ataxin-3 in Drosophila; this conclusion is also supported by genetic experiments."
ATXN3 affects mutations
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6
sparser
"Notably, increased risk of IPMN has been described in McCune-Albright syndrome, which is caused by post-zygotic mosaic autosomal dominant activating mutations of GNAS . xref , xref Oncogenic GNAS has also been identified in other tumor types including those from the pituitary, liver, and colon. xref , xref , xref "
sparser
"However, aberrant or prolonged inflammasome activation can be pathogenic, as is seen in sterile inflammatory disorders such as gout and pseudogout, and in autoinflammatory diseases caused by autosomal dominant activating mutations in inflammasome components, such as cryopyrin-associated periodic syndromes (CAPS) with mutations in NLRP3 and Familial Mediterranean Fever with mutations in MEFV ( xref , xref )."
ATXN3 affects cell population proliferation
|
6
sparser
"For instance, SLC26A4, associated with autosomal recessive NSHL xref and Pendred syndrome, is a gene coding for pendrin, a chloride/iodide transporter; COCH, responsible for autosomal dominant non syndromic post-lingual with a progressive onset in adulthood xref , encodes for cochlin, a component of the extracellular matrix of the inner ear; POU3F4, responsible for an X-linked non syndromic progressive and profound sensorineural hearing loss xref , encodes for a transcription factor; while WFS1 associated with autosomal recessive Wolfram syndrome and autosomal dominant low frequency NSHL xref , xref , is a gene coding for the glycoprotein wolframin."
ATXN3 affects UBL
|
6
sparser
"Two substitution mutations in the cystathionine-β-synthase (CBS) subdomain of IMPDH1, which are associated with human autosomal dominant retinitis pigmentosa, impair nucleic acid binding but not enzymatic activity xref , suggesting that the inability of mutant IMPDH to bind to DNA contributes to human disease."
sparser
"Whilst it may be questioned whether the treatment with BLD-2736 may have instead decreased full-length ataxin-3 through effects on the expression of EGFP-ataxin-3 via an effect on transcription, we previously demonstrated that treatment with calpeptin decreased the presence of full length human ataxin-3 protein, without altering the levels of human ataxin-3 mRNA, and that this effect was prevented by cotreatment with the autophagy inhibitor, chloroquine [ xref ]."
| PMC
sparser
"Mutations to the dynamin 2 gene ( DNM2 ) were recently associated with the autosomal dominant form of CNM while X-linked CNMs were associated with mutations in DNM2 , AMPH (amphiphysin), MTM1 (myotubularin) and most recently MTMR14 (myotubularin-related protein-14) genes (Laporte et al., xref , xref ; Jungbluth et al., xref ; Romero, xref ; Romero and Bitoun, xref )."
sparser
"Autosomal dominant centronuclear myopathy is classically associated with mutations in DNM2 which codes for dynamin 2 [ xref ], a GTPase that is involved in the mechanisms of endocytosis and transport of organelles along the network of microtubules, and also plays a key role in centrosome formation [ xref ]."
sparser
"The most common configuration for the normal allele is (CAG) 8 CAA(-CAG) 4 CAA(CAG) 8 , xref whereas the most common SCA2 pathogenic allele contains 37 uninterrupted CAG trip-lets. xref The prevalence of SCA2 is 1–2/100,000, similar to that of another form of autosomal dominant ataxia, SCA1. xref However, significant geographic and ethnic variations exist, with the prevalence reaching 41/100,000 in the Holguin region of Cuba due to a possible founder effect. xref Recently, intermediate-length ATXN2 repeat expansions (27–33 triplets), mostly interrupted by 1 to 3 CAA triplets, have been associated with an increased risk for amyotrophic lateral sclerosis (ALS). xref "
sparser
"These SCAs (SCA1–SCA3, SCA6, SCA7, and SCA17) are clinically characterized by a progressive ataxia with cerebellar degeneration that in most of these SCAs consists of severe degeneration and loss of Purkinje cells, the major integrative neuron of the cerebellar cortex ( xref ; xref )."
reach
"XREF_BIBR SCA1, SCA2, Machado-Joseph or SCA3, SCA6, SCA7, SCA12, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA) are caused by (CAG) n repeat expansions in the ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, PPP2R2B, TBP, and ATN1 genes, respectively, and all lead to the expansion of a polyglutamine tract in the corresponding proteins."
UbS2 affects ATXN3
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5
reach
"We next examined the effect of usp19 silencing on the protein levels of Atx3 100Q and Htt-N552 100Q, and observed that knockdown of USP19 significantly reduced the protein levels of Atx3 100Q (XREF_FIG) and Htt-N552 100Q (XREF_FIG) both in HEK 293T cells and in human retinal pigment epithelial (RPE1) cells (XREF_SUPPLEMENTARY)."
reach
"The regulatory function of USP19 was recently confirmed in a study demonstrating that USP19 interacts directly with chaperone Hsp90 and upregulates the aggregation of poly-Q containing the proteins Ataxin-3 and Huntingtin, which causes spinocerebellar ataxia type-3 and Huntington’s disease, respectively [90]."
sparser
"The history of “autoinflammatory diseases” dates back to the
identification of the genetic causes of the most prevalent monogenic
autoinflammatory disease worldwide, the autosomal recessive disease, familial
Mediterranean fever (FMF), in 1997, and the discovery of TNF receptor mutations in
the autosomal dominant disorder, TNF receptor associated periodic syndrome (TRAPS)
in 1999 ( xref - xref )."
sparser
"As mentioned above, both MBNL1 and 5H-4 bind to RNA12 , which contains 12 copies of the 5′C A G/3′G A C motif that is present in toxic SCA3 repeats. xref Recently, the interaction of SCA3 RNAs with Muscleblind proteins has been implicated in the disease pathology of spinocerebellar ataxia type 3. xref Therefore, we sought to study the ability of 5H-4 to inhibit SCA3 RNA-MBNL1 interactions."
reach
"Mutant (expanded) ATXN3 still binds K48- and K63 linked polyUb chains, gets activated by ubiquitination, and retains DUB catalytic activity in vitro against K48 and K63 chains similarly to normal ATXN3, but expanded ATXN3 does appear to have an enhanced capacity to deubiquitinate K27- and K29 linked Ub chains."
IU1 affects ATXN3
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5
IU1 activates ATXN3.
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3
reach
"IU1 (1-[1-(4-fluorophenyl) -2,5-dimethylpyrrol-3-yl]-2-pyrrolidin-1-ylethanone), an active-site-directed thiol protease inhibitor of USP14, was identified by a high-throughput screen and was shown to enhance degradation of tau, ataxin 3, and glial fibrillary acidic protein, independent of autophagy."
IU1 inhibits ATXN3.
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2
E4B affects ATXN3
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5
ATXN3 affects spinocerebellar ataxia type 3
|
5
ATXN3 affects localization
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5
ATXN3 activates localization. 5 / 5
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5
reach
"More evidence is needed to establish the physiological role of USP10 phosphorylation in tumorigenesis.In the case of ATX3, phosphorylation at Ser340 and Ser352 by CK2 enhances its nuclear localization, aggregation, and stability, processes that play a major role in the development of spinocerebellar ataxia-3."
sparser
"The history of “autoinflammatory diseases” dates back to the
identification of the genetic causes of the most prevalent monogenic
autoinflammatory disease worldwide, the autosomal recessive disease, familial
Mediterranean fever (FMF), in 1997, and the discovery of TNF receptor mutations in
the autosomal dominant disorder, TNF receptor associated periodic syndrome (TRAPS)
in 1999 ( xref - xref )."
reach
"Ataxin-3 has been shown to activate transcription factor forkhead box protein O4 (FOXO4) and induce the expression of manganese superoxide dismutase (SOD2), an antioxidant enzyme, under oxidative stress conditions; however, when ataxin-3 is expanded, this transcriptional activation effect is reduced and, in fact, SOD2 levels are decreased in SCA3 patients brain samples ."
reach
"Mutant (expanded) ATXN3 still binds K48- and K63 linked polyUb chains, gets activated by ubiquitination, and retains DUB catalytic activity in vitro against K48 and K63 chains similarly to normal ATXN3, but expanded ATXN3 does appear to have an enhanced capacity to deubiquitinate K27- and K29 linked Ub chains."
reach
"Altogether, our results propose a model whereby ataxin-3 increases DnaJ-1 levels in a manner that depends on the catalytic activity of this DUB and on its interaction with Rad23, and that DnaJ-1, acting downstream of the ataxin-3-Rad23 interaction, suppresses degeneration by decreasing polyQ aggregates."
ATXN3 affects DNA repair
|
5
ATXN3 activates DNA repair.
|
3
ATXN3 inhibits DNA repair.
|
2
Polyubiquitin chains affects ATXN3
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4
Hsa-miR-6851-5p affects ATXN3
4
|
Hsa-miR-6799-5p affects ATXN3
4
|
Hsa-miR-3689d affects ATXN3
4
|
sparser
"HCHWA-D is an autosomal dominant form of CAA characterized by recurrent haemorrhages due to extensive Aβ deposition in cerebral blood vessel walls and diffuse amyloid plaques but absence of dense-core senile plaques or neurofibrillary tau pathology [ xref , xref , xref ] ( xref )."
sparser
"Hereditary autosomal dominant forms of CAA, in particular the most common form of Dutch-type hereditary CAA (D-CAA; also referred to in publications as hereditary cerebral hemorrhage with amyloidosis-Dutch type, HCHWA-D), xref offer the possibility of similar investigations of the early steps in the pathogenesis of CAA."
sparser
"In fact, higher levels of Ub-Rheb were co-IPed with ATXN3 when N-Ethylmaleimide, a deubiquitinase inhibitor, was included in the lysis and purification buffers ( xref ), supporting the idea that the Ub-Rheb that binds to ATXN3 was subjected to deubiquitination during the isolation processes."
TRE affects ATXN3
|
4
sparser
"While FRO lake still clustered with JOS, fish from MAU clustered independently ( q ‐value = 0.87) but with one individual showing a F 0 immigrant profile ( q ‐value > 0.95) from the JOS‐TRE stocking group and seven other individuals showing signs of introgression (0.10 < q ‐value < 0.53) (Figure xref a,b)."
SCA2 affects ATXN3
|
4
sparser
"In fact, higher levels of Ub-Rheb were co-IPed with ATXN3 when N-Ethylmaleimide, a deubiquitinase inhibitor, was included in the lysis and purification buffers ( xref ), supporting the idea that the Ub-Rheb that binds to ATXN3 was subjected to deubiquitination during the isolation processes."
QBP1 affects ATXN3
|
4
reach
"It is conceivable that QBP1 might prevent ataxin-3 from transitioning into
these states at later time points through the interaction described here.The importance of residues outside the polyQ domain in mediating the inhibition of
aggregation reiterates the growing body of evidence for the importance of flanking
domains in modulating and controlling amyloid aggregation."
sparser
"MYH9 was an initially attractive candidate gene for kidney disease, because MYH9 mutations cause several rare diseases associated with autosomal dominant FSGS, including Fechtner syndrome and Epstein syndrome. xref , xref In further support of this association, GWAS conducted in African American and European American patients with FSGS showed that genetic variants in the region of chromosome 22 containing both MYH9 and APOL1 were strongly associated with increased risk of FSGS in African American individuals but not in European American individuals. xref However, when the DNA sequence of this region was examined in a larger, worldwide cohort, two APOL1 variants (named G1 and G2), rather than any variants in the MYH9 gene, accounted for the association with FSGS and hypertension-related kidney disease. xref These two APOL1 variants are common in African patients, but absent from European patients with FSGS."
sparser
"We further hypothesize that the MYH9 association with H-ESRD could explain the failure of intensive blood pressure reduction, including with the use of ACE inhibition, to slow nephropathy progression in hypertensive African Americans with chronic kidney disease. xref , xref , xref Prior to these reports, MYH9 was associated with rare autosomal dominant forms of macrothrombocytopenia, often with variable degrees of sensorineural deafness, cataracts, neutrophil inclusions, and glomerular disease. xref "
Josephin domain affects ATXN3
|
3
reach
"When this is actually the case, as for example in the functional interaction between EGCG or related lower-weight compounds (EG, EGC) and the Josephin domain—which triggers the amyloid aggregation in expanded ATX3 variants [165,166,167]—well-established docking approaches are able to provide detailed information on the structural basis of the action of inhibitors [113]."
sparser
"Several forms of hypophosphatemic rickets are known, including an X-linked form (MIM 307800) caused by phosphate regulating endopeptidase homolog, X-linked ( PHEX ) mutations (MIM 300550), an autosomal dominant form (MIM 193100) caused by fibroblast growth factor 23 ( FGF23 ) mutations (MIM 605380), an X-linked recessive form (MIM 300554) caused by chloride channel, voltage-sensitive 5 ( CLCN5 ) mutations (MIM 300008), and autosomal recessive forms caused by dentin matrix acidic phosphoprotein 1 ( DMP1 ) (MIM 600980), hypophosphatemic rickets, autosomal recessive 2 ( ARHR2 ) (MIM 613312) or ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) (MIM 173335) mutations. 'tiptoe walking' ( TTW ) mouse, which has a spontaneous nonsense mutation in ENPP1 is a good model for OPLL.[ xref ] Also, OPPL is a frequent complication in patients with endocrine disorders including hypoparathyroidism[ xref ] and acromegaly/gigantism.[ xref ] However, most cases of OPLL are idiopathic."
sparser
"The list of the diseases associated with OPLL includes hypophosphatemic rickets/osteomalacia, including an autosomal dominant form (MIM 193100) caused by FGF23 mutations, an X-linked dominant form (MIM 307800) caused by PHEX mutations, an X-linked recessive form (MIM 300554) caused by CLCN5 mutations, and autosomal recessive forms caused by DMP1 (MIM 600980) and ENPP1 (MIM 173335) mutations."
sparser
"Several forms of hypophosphatemic rickets are known, including an X-linked form (MIM 307800) caused by phosphate regulating endopeptidase homolog, X-linked ( PHEX ) mutations (MIM 300550), an autosomal dominant form (MIM 193100) caused by fibroblast growth factor 23 ( FGF23 ) mutations (MIM 605380), an X-linked recessive form (MIM 300554) caused by chloride channel, voltage-sensitive 5 ( CLCN5 ) mutations (MIM 300008), and autosomal recessive forms caused by dentin matrix acidic phosphoprotein 1 ( DMP1 ) (MIM 600980), hypophosphatemic rickets, autosomal recessive 2 ( ARHR2 ) (MIM 613312) or ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) (MIM 173335) mutations. 'tiptoe walking' ( TTW ) mouse, which has a spontaneous nonsense mutation in ENPP1 is a good model for OPLL.[ xref ] Also, OPPL is a frequent complication in patients with endocrine disorders including hypoparathyroidism[ xref ] and acromegaly/gigantism.[ xref ] However, most cases of OPLL are idiopathic."
sparser
"The protein is a member of the tumor necrosis factor (TNF) receptor family, and is activated by its ligand EDA and uses EDARADD as an adaptor to build an intracellular NF-kB signal-transducing complex which is necessary for normal development of ectodermal organs both in humans and in mice [ xref , xref ], Autosomal dominant (AD) forms of HED have previously been linked to mutations in the ectodysplasin 1 anhidrotic receptor (EDAR) protein but mutations in the EDAR gene are also associated with recessive forms of ED [ xref , xref ]."
sparser
"Thus, to investigate the underlying etiology of hereditary cataracts, we used embryonic stem cell-based technologies to generate knock-in mice expressing proteins harboring either the αA-R49C or αB-R120G α-crystallin mutations, which are associated with human autosomal dominant hereditary cataracts [ xref , xref ]."
ATXN3 affects polyubiquitin chains
|
4
ATXN3 affects endoplasmic reticulum
|
4
Endoplasmic reticulum binds ATXN3. 4 / 4
|
4
sparser
"The simplest explanation of these observations is that a small fraction of atx3 is transiently associated with the ER membrane via interactions with p97 and VIMP. atx3 may shuttle on and off p97 to promote PAD, a process that is linked to the ATPase cycle of p97 and to the subsequent delivery of substrates to the proteasome."
sparser
"HCHWA-D is an autosomal dominant form of CAA characterized by recurrent haemorrhages due to extensive Aβ deposition in cerebral blood vessel walls and diffuse amyloid plaques but absence of dense-core senile plaques or neurofibrillary tau pathology [ xref , xref , xref ] ( xref )."
sparser
"Hereditary autosomal dominant forms of CAA, in particular the most common form of Dutch-type hereditary CAA (D-CAA; also referred to in publications as hereditary cerebral hemorrhage with amyloidosis-Dutch type, HCHWA-D), xref offer the possibility of similar investigations of the early steps in the pathogenesis of CAA."
ATXN3 affects TRE
|
4
sparser
"While FRO lake still clustered with JOS, fish from MAU clustered independently ( q ‐value = 0.87) but with one individual showing a F 0 immigrant profile ( q ‐value > 0.95) from the JOS‐TRE stocking group and seven other individuals showing signs of introgression (0.10 < q ‐value < 0.53) (Figure xref a,b)."
ATXN3 affects SCA2
|
4
sparser
"In fact, higher levels of Ub-Rheb were co-IPed with ATXN3 when N-Ethylmaleimide, a deubiquitinase inhibitor, was included in the lysis and purification buffers ( xref ), supporting the idea that the Ub-Rheb that binds to ATXN3 was subjected to deubiquitination during the isolation processes."
ATXN3 affects Neurodegenerative Diseases
|
4
sparser
"MYH9 was an initially attractive candidate gene for kidney disease, because MYH9 mutations cause several rare diseases associated with autosomal dominant FSGS, including Fechtner syndrome and Epstein syndrome. xref , xref In further support of this association, GWAS conducted in African American and European American patients with FSGS showed that genetic variants in the region of chromosome 22 containing both MYH9 and APOL1 were strongly associated with increased risk of FSGS in African American individuals but not in European American individuals. xref However, when the DNA sequence of this region was examined in a larger, worldwide cohort, two APOL1 variants (named G1 and G2), rather than any variants in the MYH9 gene, accounted for the association with FSGS and hypertension-related kidney disease. xref These two APOL1 variants are common in African patients, but absent from European patients with FSGS."
sparser
"We further hypothesize that the MYH9 association with H-ESRD could explain the failure of intensive blood pressure reduction, including with the use of ACE inhibition, to slow nephropathy progression in hypertensive African Americans with chronic kidney disease. xref , xref , xref Prior to these reports, MYH9 was associated with rare autosomal dominant forms of macrothrombocytopenia, often with variable degrees of sensorineural deafness, cataracts, neutrophil inclusions, and glomerular disease. xref "
sparser
"Several forms of hypophosphatemic rickets are known, including an X-linked form (MIM 307800) caused by phosphate regulating endopeptidase homolog, X-linked ( PHEX ) mutations (MIM 300550), an autosomal dominant form (MIM 193100) caused by fibroblast growth factor 23 ( FGF23 ) mutations (MIM 605380), an X-linked recessive form (MIM 300554) caused by chloride channel, voltage-sensitive 5 ( CLCN5 ) mutations (MIM 300008), and autosomal recessive forms caused by dentin matrix acidic phosphoprotein 1 ( DMP1 ) (MIM 600980), hypophosphatemic rickets, autosomal recessive 2 ( ARHR2 ) (MIM 613312) or ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) (MIM 173335) mutations. 'tiptoe walking' ( TTW ) mouse, which has a spontaneous nonsense mutation in ENPP1 is a good model for OPLL.[ xref ] Also, OPPL is a frequent complication in patients with endocrine disorders including hypoparathyroidism[ xref ] and acromegaly/gigantism.[ xref ] However, most cases of OPLL are idiopathic."
sparser
"The list of the diseases associated with OPLL includes hypophosphatemic rickets/osteomalacia, including an autosomal dominant form (MIM 193100) caused by FGF23 mutations, an X-linked dominant form (MIM 307800) caused by PHEX mutations, an X-linked recessive form (MIM 300554) caused by CLCN5 mutations, and autosomal recessive forms caused by DMP1 (MIM 600980) and ENPP1 (MIM 173335) mutations."
sparser
"Several forms of hypophosphatemic rickets are known, including an X-linked form (MIM 307800) caused by phosphate regulating endopeptidase homolog, X-linked ( PHEX ) mutations (MIM 300550), an autosomal dominant form (MIM 193100) caused by fibroblast growth factor 23 ( FGF23 ) mutations (MIM 605380), an X-linked recessive form (MIM 300554) caused by chloride channel, voltage-sensitive 5 ( CLCN5 ) mutations (MIM 300008), and autosomal recessive forms caused by dentin matrix acidic phosphoprotein 1 ( DMP1 ) (MIM 600980), hypophosphatemic rickets, autosomal recessive 2 ( ARHR2 ) (MIM 613312) or ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) (MIM 173335) mutations. 'tiptoe walking' ( TTW ) mouse, which has a spontaneous nonsense mutation in ENPP1 is a good model for OPLL.[ xref ] Also, OPPL is a frequent complication in patients with endocrine disorders including hypoparathyroidism[ xref ] and acromegaly/gigantism.[ xref ] However, most cases of OPLL are idiopathic."
ATXN3 affects ERAD
|
4
sparser
"The protein is a member of the tumor necrosis factor (TNF) receptor family, and is activated by its ligand EDA and uses EDARADD as an adaptor to build an intracellular NF-kB signal-transducing complex which is necessary for normal development of ectodermal organs both in humans and in mice [ xref , xref ], Autosomal dominant (AD) forms of HED have previously been linked to mutations in the ectodysplasin 1 anhidrotic receptor (EDAR) protein but mutations in the EDAR gene are also associated with recessive forms of ED [ xref , xref ]."
sparser
"Thus, to investigate the underlying etiology of hereditary cataracts, we used embryonic stem cell-based technologies to generate knock-in mice expressing proteins harboring either the αA-R49C or αB-R120G α-crystallin mutations, which are associated with human autosomal dominant hereditary cataracts [ xref , xref ]."
sparser
"Asking whether aggregated proteins are asymmetrically inherited in polarized living tissue, the investigators studied human intestinal crypts of patient with spinocerebellar ataxia 3, a neurodegenerative disease associated with the accumulation of ataxin-3 polyglutamine-containing protein."
sparser
"We focus on the nine neurodegenerative disorders caused by expansions of polyglutamine (polyQ) tracts, including spinal and bulbar muscular atrophy (SBMA), Huntington’s disease (HD), dentatorubropallidoluysian atrophy (DRPLA), and six autosomal dominant forms of spinocerebellar ataxia (SCA1, 2, 3, 6, 7, and 17)."
ATXN3 affects ANT1
|
4
sparser
"In humans, ANT1 mutations have been associated with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions ( xref ) as well as autosomal recessive hypertrophic cardiomyopathy, myopathy, and lactic acidosis ( xref ). kdn encodes the Kreb cycle enzyme, citrate synthase."
reach
"XREF_BIBR SCA1, SCA2, Machado-Joseph or SCA3, SCA6, SCA7, SCA12, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA) are caused by (CAG) n repeat expansions in the ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, PPP2R2B, TBP, and ATN1 genes, respectively, and all lead to the expansion of a polyglutamine tract in the corresponding proteins."
sparser
"Asking whether aggregated proteins are asymmetrically inherited in polarized living tissue, the investigators studied human intestinal crypts of patient with spinocerebellar ataxia 3, a neurodegenerative disease associated with the accumulation of ataxin-3 polyglutamine-containing protein."
sparser
"We focus on the nine neurodegenerative disorders caused by expansions of polyglutamine (polyQ) tracts, including spinal and bulbar muscular atrophy (SBMA), Huntington’s disease (HD), dentatorubropallidoluysian atrophy (DRPLA), and six autosomal dominant forms of spinocerebellar ataxia (SCA1, 2, 3, 6, 7, and 17)."
ANT1 affects ATXN3
|
4
sparser
"In humans, ANT1 mutations have been associated with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions ( xref ) as well as autosomal recessive hypertrophic cardiomyopathy, myopathy, and lactic acidosis ( xref ). kdn encodes the Kreb cycle enzyme, citrate synthase."
Temsirolimus affects ATXN3
|
3
P97 affects ATXN3
|
3
sparser
"Interestingly, mutation in the VBM motif of Atx3 100Q (Atx3 100Q /VBM*, 282 RKRR to HNHH), which disrupts the specific interaction between Atx3 and P97, significantly abolished the sequestration of P97 into aggregates; even the amount of P97 sequestered by the mutant was less than that by Atx3 22Q under the condition of similar amounts of the Atx3 aggregates ( xref )."
sparser
"Although it cannot be excluded that the lower amount of the aggregates may have some correlation to the decreased sequestration, we think that the major contribution to the decreased ability of the VBM mutant to sequester P97 is from disruption of the specific interaction between Atx3 100Q and P97."
Hsa-miR-921 affects ATXN3
3
|
Hsa-miR-6134 affects ATXN3
3
|
Hsa-miR-6073 affects ATXN3
3
|
Hsa-miR-4537 affects ATXN3
3
|
Hsa-miR-382-5p affects ATXN3
3
|
Hsa-miR-3190-3p affects ATXN3
3
|
Hsa-miR-3174 affects ATXN3
3
|
Hsa-miR-142-3p affects ATXN3
3
|
Hsa-miR-1247-3p affects ATXN3
3
|
VCP affects RAD23 family
|
3
sparser
"The role of UMOD in normal kidney function is incompletely understood, however, mutations of the UMOD gene are associated with autosomal dominant tubulointerstitial kidney disease (ADTKD- UMOD ) which as previously been known as familial juvenile hyperuricaemic nephropathy (FJHN) and medullary cystic kidney disease (MCKD2), also known as UMOD-associated kidney diseases [ xref , xref , xref , xref , xref ]."
sparser
"It should
be noted, however, that irrespective of genetic phenotypes, in both CHD populations
and cohorts with established Autosomal Dominant Tubulointerstitial Kidney Disease
(ADTKD-UMOD), serum uromodulin concentrations were independently associated with
hard outcomes in the former [ xref ], or were
lower in all affected patients with a novel missense mutation in the UMOD gene
(457T>G; Cys153Gly), relative to all patients of the reference eGFR-matched
CKD groups, and healthy, unaffected family members [ xref ]."
sparser
"Indeed, patients with the autosomal dominant form of hyper IgE syndrome (HIES) have severely reduced numbers of IL-17 producing circulating T cells due to dominant-negative mutations of the signal transducer and activator of transcription 3 ( STAT3 ), and often suffer from CMC [ xref – xref ]."
sparser
"Brugada syndrome is a life-threatening, inherited arrhythmia disorder associated with autosomal dominant mutations in SCN5A [ xref - xref ], the gene encoding the human cardiac Na + channel α subunit (Nav1.5) [ xref ], which contains four homologous domains, each composed of six membrane-spanning segments, linked by cytoplasmic linkers."
RAD23 family affects VCP
|
3
PPK affects ATXN3
|
3
sparser
"Mutations in human NOTCH3 are associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a disorder that causes stroke and dementia and is accompanied by the degeneration of vascular smooth muscle cells [ xref ]; adult Notch3 mutant mice display a defect in the maturation of arterial smooth muscle cells [ xref ]."
sparser
"Further, it was shown that both normal and expanded ataxin 3 physiologically interact with HDAC3 and NCoR in a SCA3 cell model and in human pons tissue; however, normal ataxin 3-containing protein complexes showed increased histone deacetylase activity, whereas polyglutamine-expanded ataxin 3-containing complexes had reduced deacetylase activity in target chromatin regions [ xref ]."
K63 affects K48-
|
3
reach
"Mutant (expanded) ATXN3 still binds K48- and K63 linked polyUb chains, gets activated by ubiquitination, and retains DUB catalytic activity in vitro against K48 and K63 chains similarly to normal ATXN3, but expanded ATXN3 does appear to have an enhanced capacity to deubiquitinate K27- and K29 linked Ub chains."
sparser
"The few studies on the relative frequency of these disorders indicate that the most frequent (or rather the least rare), accounting for more than half of patients, is CADASIL, due to mutations of the NOTCH3 gene, followed by COL4A1/A2-related disease, autosomal dominant forms of HTRA1-related disease and leucoencephalopathies with calcifications and cysts."
sparser
"Further, it was shown that both normal and expanded ataxin 3 physiologically interact with HDAC3 and NCoR in a SCA3 cell model and in human pons tissue; however, normal ataxin 3-containing protein complexes showed increased histone deacetylase activity, whereas polyglutamine-expanded ataxin 3-containing complexes had reduced deacetylase activity in target chromatin regions [ xref ]."
sparser
"A robust increase (64–94%) in the number of histamine neurons in the TMN has been reported by two independent groups ( xref ). xref , xref However, we did not observe this increase of histamine neurons in a series of narcoleptic animal models we tested (hypocretin 2R mutant dogs, Hcrt knock-out mice, ataxin-3-hypocretin mice, and doxycycline-controlled diphtheria toxin A–hypocretin mice). xref Of these animal models, the postnatal hypocretin cell loss and adult-onset symptoms seen in the doxycycline-controlled diphtheria toxin A–hypocretin mouse resembles the clinical characteristics human narcolepsy most closely. xref Valko et al . reported only a small increase in the number of histamine cells in the Hcrt knockout mice, but not in the ataxin-3-hypocretin mouse. xref These data lead us to conclude that the large increase in histamine neurons in human patients with narcolepsy is not a compensation for the loss of hypocretin neurons."
sparser
"Interestingly, this increase in REM sleep during the subjective dark period was originally shown in orexin-ataxin-3 mice but not orexin knockout mice, which was thought to indicate an effect of the loss of orexin neurons as opposed to the loss of the orexin peptides per se (Kantor et al., 2009)."
reach
"Interestingly, mutation in the VBM motif of Atx3 100Q (Atx3 100Q / VBM *, 282 RKRR to HNHH), which disrupts the specific interaction between Atx3 and P97, significantly abolished the sequestration of P97 into aggregates; even the amount of P97 sequestered by the mutant was less than that by Atx3 22Q under the condition of similar amounts of the Atx3 aggregates (XREF_FIG)."
sparser
"Specific germline point mutations affecting differing domains of the FGFR3 gene are associated with several autosomal dominant skeletal dysplasias: dwarfism and several craniosynostosis syndromes including hypochondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), thantophoric dysplasia, Crouzon syndrome with acanthosis nigricans, and coronal craniosynostosis. xref – xref The same mutations that are seen in these skeletal dysplasias have also been identified in several human cancers and thus it has also been suggested that FGFR3 mutations may be oncogenic xref ."
DCM affects ATXN3
|
3
sparser
"In an autosomal dominant form of DCM caused by mutations in the RNA‐binding motif protein 20 gene ( RBM20 ), for example, stage‐specific transcriptome profiling demonstrated early molecular perturbations during cardiogenesis in patient‐specific hiPSCs xref ; these results suggested that this clinically aggressive form of DCM is a developmental disorder."
sparser
"Mutations in these genes are found to be associated either with different forms of autosomal dominant Wolfram syndrome, autosomal recessive spinocerebellar ataxia-1/autosomal dominant juvenile amyotrophic lateral sclerosis type 4, or manifesting clinically as types of hemolytic anemia, features not observed in these isolated CE patients."
reach
"Activation has also been reported for other deubiquitinating enzymes XREF_BIBR - XREF_BIBR and most recently, a synergistic cooperation between ataxin-3 and CDC-48 (C. elegans orthologue of VCP and p97) was found to have a role in ageing regulation and ubiquitin mediated proteolysis in C. elegans XREF_BIBR."
sparser
"The most common configuration for the normal allele is (CAG) 8 CAA(-CAG) 4 CAA(CAG) 8 , xref whereas the most common SCA2 pathogenic allele contains 37 uninterrupted CAG trip-lets. xref The prevalence of SCA2 is 1–2/100,000, similar to that of another form of autosomal dominant ataxia, SCA1. xref However, significant geographic and ethnic variations exist, with the prevalence reaching 41/100,000 in the Holguin region of Cuba due to a possible founder effect. xref Recently, intermediate-length ATXN2 repeat expansions (27–33 triplets), mostly interrupted by 1 to 3 CAA triplets, have been associated with an increased risk for amyotrophic lateral sclerosis (ALS). xref "
sparser
"These SCAs (SCA1–SCA3, SCA6, SCA7, and SCA17) are clinically characterized by a progressive ataxia with cerebellar degeneration that in most of these SCAs consists of severe degeneration and loss of Purkinje cells, the major integrative neuron of the cerebellar cortex ( xref ; xref )."
BLD-2736 affects ATXN3
|
3
reach
"Whilst it may be questioned whether the treatment with BLD-2736 may have instead decreased full-length ataxin-3 through effects on the expression of EGFP-ataxin-3 via an effect on transcription, we previously demonstrated that treatment with calpeptin decreased the presence of full length human ataxin-3 protein, without altering the levels of human ataxin-3 mRNA, and that this effect was prevented by cotreatment with the autophagy inhibitor, chloroquine [43]."
| PMC
ATXN3 affects pathway
|
3
ATXN3 affects p97
|
3
sparser
"Interestingly, mutation in the VBM motif of Atx3 100Q (Atx3 100Q /VBM*, 282 RKRR to HNHH), which disrupts the specific interaction between Atx3 and P97, significantly abolished the sequestration of P97 into aggregates; even the amount of P97 sequestered by the mutant was less than that by Atx3 22Q under the condition of similar amounts of the Atx3 aggregates ( xref )."
sparser
"Although it cannot be excluded that the lower amount of the aggregates may have some correlation to the decreased sequestration, we think that the major contribution to the decreased ability of the VBM mutant to sequester P97 is from disruption of the specific interaction between Atx3 100Q and P97."
sparser
"The role of UMOD in normal kidney function is incompletely understood, however, mutations of the UMOD gene are associated with autosomal dominant tubulointerstitial kidney disease (ADTKD- UMOD ) which as previously been known as familial juvenile hyperuricaemic nephropathy (FJHN) and medullary cystic kidney disease (MCKD2), also known as UMOD-associated kidney diseases [ xref , xref , xref , xref , xref ]."
sparser
"It should
be noted, however, that irrespective of genetic phenotypes, in both CHD populations
and cohorts with established Autosomal Dominant Tubulointerstitial Kidney Disease
(ADTKD-UMOD), serum uromodulin concentrations were independently associated with
hard outcomes in the former [ xref ], or were
lower in all affected patients with a novel missense mutation in the UMOD gene
(457T>G; Cys153Gly), relative to all patients of the reference eGFR-matched
CKD groups, and healthy, unaffected family members [ xref ]."
sparser
"Indeed, patients with the autosomal dominant form of hyper IgE syndrome (HIES) have severely reduced numbers of IL-17 producing circulating T cells due to dominant-negative mutations of the signal transducer and activator of transcription 3 ( STAT3 ), and often suffer from CMC [ xref – xref ]."
sparser
"Brugada syndrome is a life-threatening, inherited arrhythmia disorder associated with autosomal dominant mutations in SCN5A [ xref - xref ], the gene encoding the human cardiac Na + channel α subunit (Nav1.5) [ xref ], which contains four homologous domains, each composed of six membrane-spanning segments, linked by cytoplasmic linkers."
ATXN3 affects RAD23 family, and VCP
|
3
ATXN3 affects PPK
|
3
ATXN3 affects Neoplasm Metastasis
|
3
sparser
"Mutations in human NOTCH3 are associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a disorder that causes stroke and dementia and is accompanied by the degeneration of vascular smooth muscle cells [ xref ]; adult Notch3 mutant mice display a defect in the maturation of arterial smooth muscle cells [ xref ]."
ATXN3 affects Machado-Joseph disease
|
3
sparser
"As mentioned above, both MBNL1 and 5H-4 bind to RNA12 , which contains 12 copies of the 5′C A G/3′G A C motif that is present in toxic SCA3 repeats. xref Recently, the interaction of SCA3 RNAs with Muscleblind proteins has been implicated in the disease pathology of spinocerebellar ataxia type 3. xref Therefore, we sought to study the ability of 5H-4 to inhibit SCA3 RNA-MBNL1 interactions."
reach
"XREF_BIBR SCA1, SCA2, Machado-Joseph or SCA3, SCA6, SCA7, SCA12, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA) are caused by (CAG) n repeat expansions in the ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, PPP2R2B, TBP, and ATN1 genes, respectively, and all lead to the expansion of a polyglutamine tract in the corresponding proteins."
ATXN3 affects K48-, and K63
|
3
reach
"Mutant (expanded) ATXN3 still binds K48- and K63 linked polyUb chains, gets activated by ubiquitination, and retains DUB catalytic activity in vitro against K48 and K63 chains similarly to normal ATXN3, but expanded ATXN3 does appear to have an enhanced capacity to deubiquitinate K27- and K29 linked Ub chains."
ATXN3 affects Interferon
|
3
ATXN3 activates Interferon. 3 / 3
|
3
reach
"Unlike USP2A, the deubiquitinating enzymes BRCC36, USP13, and USP39 positively regulate IFN activities by attenuating the polyubiquitination level of STAT1, and this process is independent of IFN treatment, which suggests divergent functional roles of these DUBs under differential contexts.Additionally, ATXN3 does not affect IFN-I production during viral infection but positively regulates IFNAR1-mediated downstream signaling by targeting HDAC3 (108)."
sparser
"The few studies on the relative frequency of these disorders indicate that the most frequent (or rather the least rare), accounting for more than half of patients, is CADASIL, due to mutations of the NOTCH3 gene, followed by COL4A1/A2-related disease, autosomal dominant forms of HTRA1-related disease and leucoencephalopathies with calcifications and cysts."
ATXN3 affects HSJ1a
|
1
2
sparser
"Further, it was shown that both normal and expanded ataxin 3 physiologically interact with HDAC3 and NCoR in a SCA3 cell model and in human pons tissue; however, normal ataxin 3-containing protein complexes showed increased histone deacetylase activity, whereas polyglutamine-expanded ataxin 3-containing complexes had reduced deacetylase activity in target chromatin regions [ xref ]."
sparser
"A robust increase (64–94%) in the number of histamine neurons in the TMN has been reported by two independent groups ( xref ). xref , xref However, we did not observe this increase of histamine neurons in a series of narcoleptic animal models we tested (hypocretin 2R mutant dogs, Hcrt knock-out mice, ataxin-3-hypocretin mice, and doxycycline-controlled diphtheria toxin A–hypocretin mice). xref Of these animal models, the postnatal hypocretin cell loss and adult-onset symptoms seen in the doxycycline-controlled diphtheria toxin A–hypocretin mouse resembles the clinical characteristics human narcolepsy most closely. xref Valko et al . reported only a small increase in the number of histamine cells in the Hcrt knockout mice, but not in the ataxin-3-hypocretin mouse. xref These data lead us to conclude that the large increase in histamine neurons in human patients with narcolepsy is not a compensation for the loss of hypocretin neurons."
sparser
"Interestingly, this increase in REM sleep during the subjective dark period was originally shown in orexin-ataxin-3 mice but not orexin knockout mice, which was thought to indicate an effect of the loss of orexin neurons as opposed to the loss of the orexin peptides per se (Kantor et al., 2009)."
sparser
"Specific germline point mutations affecting differing domains of the FGFR3 gene are associated with several autosomal dominant skeletal dysplasias: dwarfism and several craniosynostosis syndromes including hypochondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), thantophoric dysplasia, Crouzon syndrome with acanthosis nigricans, and coronal craniosynostosis. xref – xref The same mutations that are seen in these skeletal dysplasias have also been identified in several human cancers and thus it has also been suggested that FGFR3 mutations may be oncogenic xref ."
ATXN3 affects DCM
|
3
sparser
"In an autosomal dominant form of DCM caused by mutations in the RNA‐binding motif protein 20 gene ( RBM20 ), for example, stage‐specific transcriptome profiling demonstrated early molecular perturbations during cardiogenesis in patient‐specific hiPSCs xref ; these results suggested that this clinically aggressive form of DCM is a developmental disorder."
reach
"While it is reasonable to hypothesize that expanded Ataxin-3 protein may activate caspases that proteolyze Ataxin-3, the observation that normal Ataxin-3, which does not cause neurodegeneration, is also cleaved, suggests that cleavage is not necessarily a consequence of apoptosis."
sparser
"While it is reasonable to hypothesize that expanded Ataxin-3 protein may activate caspases that proteolyze Ataxin-3, the observation that normal Ataxin-3, which does not cause neurodegeneration, is also cleaved, suggests that cleavage is not necessarily a consequence of apoptosis."
sparser
"Mutations in these genes are found to be associated either with different forms of autosomal dominant Wolfram syndrome, autosomal recessive spinocerebellar ataxia-1/autosomal dominant juvenile amyotrophic lateral sclerosis type 4, or manifesting clinically as types of hemolytic anemia, features not observed in these isolated CE patients."
reach
"Activation has also been reported for other deubiquitinating enzymes XREF_BIBR - XREF_BIBR and most recently, a synergistic cooperation between ataxin-3 and CDC-48 (C. elegans orthologue of VCP and p97) was found to have a role in ageing regulation and ubiquitin mediated proteolysis in C. elegans XREF_BIBR."
ATXN3 affects AAA ATPase
|
3
AAA ATPase affects ATXN3
|
3
Ubiquitin-like domain affects ATXN3
|
2
Transcriptional regulator affects ATXN3
|
2
ATXN3 binds transcriptional regulator. 2 / 2
|
2
sparser
"Ataxin-3 normally interacts with numerous transcriptional regulators including the forkhead box O (FOXO)-4 transcription factor, TATA-binding protein-associated factor TAFII130 [ xref ], CBP [ xref ], nuclear co-repressor receptor NCoR [ xref ], histone deacetylases [ xref ], and DNA repair protein RAD23 [ xref ]."
sparser
"The autosomal dominant form of STL is caused by mutations in COL2A1 [ xref ], COL11A1 [ xref ], or COL11A2 (Gene ID 1302, OMIM) [ xref ], while the autosomal recessive form of STL is caused by mutations in COL9A1 (Gene ID 12839, OMIM) [ xref ], COL9A2 (Gene ID 1298, OMIM) [ xref ], COL9A3 (Gene ID 1299, OMIM) [ xref ], or LOXL3 (Gene ID 84695, OMIM) [ xref , xref ]."
Resveratrol affects ATXN3
1
|
1
Poly-ubiquitin chains affects ATXN3
|
2
Phenylmercury acetate affects ATXN3
2
|
Monoubiquitin affects ATXN3
|
1
1
Magnetite nanoparticle affects ATXN3
2
|
Low-density lipoprotein affects PCSK9
|
2
Hsa-miR-8485 affects ATXN3
2
|
Hsa-miR-603 affects ATXN3
2
|
Hsa-miR-5011-5p affects ATXN3
2
|
Hsa-miR-4789-5p affects ATXN3
2
|
Hsa-miR-4789-3p affects ATXN3
2
|
Hsa-miR-3941 affects ATXN3
2
|
Hsa-miR-362-3p affects ATXN3
2
|
Hsa-miR-329-3p affects ATXN3
2
|
Hsa-miR-190a-3p affects ATXN3
2
|
Hsa-miR-1277-5p affects ATXN3
2
|
Endocrine affects ATXN3
|
2
Dynein affects ATXN3
|
1
Crystallin affects ATXN3
|
2
Arginine affects VCP
|
2
Aflatoxin B1 affects ATXN3
2
|
VCP affects arginine
|
2
UBL affects PRKN
|
2
sparser
"Cowden syndrome (CS), an autosomal dominant disease associated with mutations in the PTEN tumor suppressor gene on chromosome 10q10.22-23, is associated with elevated risks of breast and thyroid cancer, as well as diverse benign neoplasms including gastrointestinal hamartomatous polyps, lipomas, giant fibroadenomas of the breast, hemangiomas, and multiple early-onset uterine leiomyomas [ xref ]."
sparser
"The PEO1 ( C10ORF2 ) mutations are associated with autosomal dominant progressive external ophthalmoplegia (PEO) (PEOA3), parkinsonism, as well as infantileonset spinocerebellar ataxia. xref , xref , xref Biochemical analyses of purified mutant PEO1 proteins have been performed, but the results have been mixed. xref , xref , xref The functional defects of mutant Twinkle proteins have also been studied in the ortholog in Drosophila . xref Transgenic mice carrying a point mutation at amino acid residue 360 (A360T), or a short repeat of amino acids 353 to 365 reproduced histopathology and histochemical changes resulting from mitochondrial respiratory chain dysfunction."
sparser
"TWNK was also associated with autosomal dominant progressive external ophthalmoplegia (adPEO, OMIM #609286) which can result in ophthalmoparesis with exercise intolerance, ataxia, peripheral neuropathy and multiple mtDNA deletions and at least 40 causative mutations for adPEO have been identified up to now [ xref ]."
reach
"Genes that were part of this signature on the brain side were the TCF4, ATN1, PPP2R2B, ATXN10 and ATXN3, which are associated with neurodegenerative and developmental disorders such as Pitt-Hopkins Syndrome [XREF_BIBR], Dentatorubral pallidoluysian atrophy [XREF_BIBR], SCA12 [XREF_BIBR], SCA10 [XREF_BIBR] and SCA3 [XREF_BIBR]."
reach
"STB/HAP1 can also interact with the causal agents of some other polyQ diseases, such as with Abelson helper integration site 1 in Joubert syndrome (Sheng et al., 2008), ataxin 3 in Machado-Joseph disease (Takeshita et al., 2011) and TATA binding protein in spinocerebellar ataxia type 17 (Prigge and Schmidt, 2007)."
sparser
"There are several DNA tests currently available that are based on dominant or codominant mutations, including the RHO mutation for an autosomal dominant form of PRA in the English Mastiff offered by OptiGen () (Kijas et al. xref ), the mutation in HSF4 that is associated with hereditary cataract in the Australian Shepherd that is offered by the Animal Health Trust () (Mellersh et al. xref , xref ), and the polymorphisms associated with renal dysplasia in multiple breeds that is offered by DoGenes () (Whiteley et al. xref )."
sparser
"Deleterious mutations in RUNX1 (Runt-related transcription factor 1; MIM ID *151385) are associated with a rare Autosomal Dominant hereditary cancer syndrome (linked to 21q22.12) that is characterized by qualitative and quantitative platelet defects with a high-propensity for myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and lymphoid malignancies( xref )."
sparser
"In humans, heterozygous RUNX1 mutation is associated with an autosomal dominant disorder, the familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) (Mendelian Inheritance in Man [MIM] 601399), characterized by impaired megakaryopoiesis, quantitative and qualitative defects in platelet function, and over 40% risk of development of myelodysplastic syndrome (MDS) or AML at a median age of 33 years [ xref – xref ]."
RNA-binding affects ATXN3
|
2
reach
"In addition, several groups demonstrated that inhibition of the proteasome in cell culture and mammalian cells results in increased aggregation and cytotoxicity in SCA 3 and HD [XREF_BIBR, XREF_BIBR], whereas an overexpression of p45 (ATPase of 19S subunit of proteasome) stimulates degradation of ataxin-3 [XREF_BIBR]."
sparser
" PROM1 (OMIM 612657) codes for a transmembrane glycoprotein (Prominin-1) that localizes to the base of the rod and cone outer segments and is involved in disc assembly and maintenance of outer segment structure. xref PROM1 is associated with both autosomal dominant (AD) xref , xref and AR xref retinal dystrophies, with the AD forms tending to be later onset and milder. xref PROM1 is responsible for between 1.0% and 9.5% of AR CRD (arCRD) cases. xref , xref , xref "
PRKN affects UBL
|
2
sparser
"PNKP has been shown to promote transcription-coupled double-strand break repair ( xref ) and often performs transcription-coupled repair when in complex with huntingtin protein, RNA polymerase II subunit A, ataxin-3, and cyclic AMP-response element binding protein (CBP) ( xref )."
sparser
"The mechanisms for this were recently suggested to be through direct interactions between HTT and RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP) [ xref ], as well as complexes with the DNA double-strand break repair complex Ku70/Ku80 [ xref ]."
PLD affects ATXN3
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2
sparser
"Furthermore, the altered pitx2 expression pattern, together with the described morphological features of the lens-ablated fish suggests that Astyanax mexicanus could be considered as an alternative teleost model organism in which to study Axenfeld-Rieger syndrome (ARS), a rare autosomal dominant developmental disorder that is associated with PITX2 and which has both ocular and non-ocular abnormalities."
sparser
"The list of the diseases associated with OPLL includes hypophosphatemic rickets/osteomalacia, including an autosomal dominant form (MIM 193100) caused by FGF23 mutations, an X-linked dominant form (MIM 307800) caused by PHEX mutations, an X-linked recessive form (MIM 300554) caused by CLCN5 mutations, and autosomal recessive forms caused by DMP1 (MIM 600980) and ENPP1 (MIM 173335) mutations."
sparser
"Several forms of hypophosphatemic rickets are known, including an X-linked form (MIM 307800) caused by phosphate regulating endopeptidase homolog, X-linked ( PHEX ) mutations (MIM 300550), an autosomal dominant form (MIM 193100) caused by fibroblast growth factor 23 ( FGF23 ) mutations (MIM 605380), an X-linked recessive form (MIM 300554) caused by chloride channel, voltage-sensitive 5 ( CLCN5 ) mutations (MIM 300008), and autosomal recessive forms caused by dentin matrix acidic phosphoprotein 1 ( DMP1 ) (MIM 600980), hypophosphatemic rickets, autosomal recessive 2 ( ARHR2 ) (MIM 613312) or ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) (MIM 173335) mutations. 'tiptoe walking' ( TTW ) mouse, which has a spontaneous nonsense mutation in ENPP1 is a good model for OPLL.[ xref ] Also, OPPL is a frequent complication in patients with endocrine disorders including hypoparathyroidism[ xref ] and acromegaly/gigantism.[ xref ] However, most cases of OPLL are idiopathic."
PCSK9 affects low-density lipoprotein
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2
Machado-Joseph Disease affects ATXN3
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2
sparser
"For example, causal variants in the MUC1 gene, which is associated with autosomal dominant tubulointerstitial kidney disease (ADTKD- MUC1 ; OMIM 174000) and contains a highly repetitive, GC-rich sequence, were missed by NGS-based regional capture, WES, and WGS and were identified only by long-range PCR and molecular cloning xref ."
reach
"For instance, both mutant SOD1, a misfolded mitochondrial protein associated with the onset of amyotrophic lateral sclerosis, and polyglutamine expanded ataxin-3, a pathogenic protein causing Machado-Joseph disease, are ubiquitinated by MITOL and then degraded by the proteasome [XREF_BIBR - XREF_BIBR]."
sparser
"Initial translational efforts might, therefore, be more successful in disorders with more homogeneous underlying pathology, such as the primary tauopathies, progressive supranuclear palsy (PSP) and autosomal dominant frontotemporal lobar degeneration (FTLD) associated with MAPT mutations, in all of which tau is the major abnormal protein."
sparser
"FPLD (MIM 151660) is a rare autosomal dominant form of insulin resistance caused by mutant LMNA, which encodes nuclear lamin A/C, a structural component of the nuclear envelope.[ xref ] FPLD is characterized by loss of fat affecting the limbs and trunk, accumulation of fat in the neck and face, and predisposition to insulin resistance, leading to complications such as glucose intolerance, dyslipidemia, high blood pressure, liver steatosis, and increased risk for coronary heart disease."
LC3C affects ATXN3
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2
sparser
"PNKP has been shown to promote transcription-coupled double-strand break repair ( xref ) and often performs transcription-coupled repair when in complex with huntingtin protein, RNA polymerase II subunit A, ataxin-3, and cyclic AMP-response element binding protein (CBP) ( xref )."
sparser
"The mechanisms for this were recently suggested to be through direct interactions between HTT and RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP) [ xref ], as well as complexes with the DNA double-strand break repair complex Ku70/Ku80 [ xref ]."
HHR23 affects ATXN3
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2
sparser
"Finally, mutations causing the autosomal dominant form of dopa-responsive dystonia have been identified in the gene coding for GTP cyclohydrolase I. Mutations in tyrosine hydroxylase have been identified in two brothers and put forward as evidence of an autosomal recessive form of the disease."
sparser
"The list of the diseases associated with OPLL includes hypophosphatemic rickets/osteomalacia, including an autosomal dominant form (MIM 193100) caused by FGF23 mutations, an X-linked dominant form (MIM 307800) caused by PHEX mutations, an X-linked recessive form (MIM 300554) caused by CLCN5 mutations, and autosomal recessive forms caused by DMP1 (MIM 600980) and ENPP1 (MIM 173335) mutations."
sparser
"Several forms of hypophosphatemic rickets are known, including an X-linked form (MIM 307800) caused by phosphate regulating endopeptidase homolog, X-linked ( PHEX ) mutations (MIM 300550), an autosomal dominant form (MIM 193100) caused by fibroblast growth factor 23 ( FGF23 ) mutations (MIM 605380), an X-linked recessive form (MIM 300554) caused by chloride channel, voltage-sensitive 5 ( CLCN5 ) mutations (MIM 300008), and autosomal recessive forms caused by dentin matrix acidic phosphoprotein 1 ( DMP1 ) (MIM 600980), hypophosphatemic rickets, autosomal recessive 2 ( ARHR2 ) (MIM 613312) or ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) (MIM 173335) mutations. 'tiptoe walking' ( TTW ) mouse, which has a spontaneous nonsense mutation in ENPP1 is a good model for OPLL.[ xref ] Also, OPPL is a frequent complication in patients with endocrine disorders including hypoparathyroidism[ xref ] and acromegaly/gigantism.[ xref ] However, most cases of OPLL are idiopathic."
Dnmt1 affects UBL
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2
DSBs affects ATXN3
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2
sparser
"Germline mutations in DICER1 are associated with an autosomal dominant hereditary cancer predisposition syndrome that confers an increased risk for the development of several rare childhood and adult-onset tumors, the most frequent of which include pleuropulmonary blastoma, ovarian sex cord-stromal tumors, cystic nephroma, and thyroid gland neoplasia."
reach
"Whilst it may be questioned whether the treatment with BLD-2736 may have instead decreased full-length ataxin-3 through effects on the expression of EGFP-ataxin-3 via an effect on transcription, we previously demonstrated that treatment with calpeptin decreased the presence of full length human ataxin-3 protein, without altering the levels of human ataxin-3 mRNA, and that this effect was prevented by cotreatment with the autophagy inhibitor, chloroquine [43]."
| PMC
sparser
"Mutations in human CRX (NCBI Reference Sequence: NG_008605.1) have been associated with autosomal dominant forms of the retinal degenerative diseases Retinitis Pigmentosa (adRP), Cone-Rod Dystrophy (adCoRD) and Leber Congenital Amaurosis (adLCA), with different ages of onset and severity xref xref – xref ."
sparser
"Lynch syndrome (LS) or hereditary non-polyposis colorectal cancer, is an autosomal dominant form of CRC that may account for up to 5% of all CRC cases. xref The penetrance for development of malignancy is up to 68.7% in males and 52% in females. xref Founder effects for LS have been discovered in several populations, including Newfoundland, Canada. xref It is believed that the increased rates of CRC in this province, which are among the highest in the world, may be attributable to a high rate of familial cancer in the population and possibly to the presence of novel susceptibility genes. xref , xref Familial adenomatous polyposis is another autosomal dominant inherited syndrome that greatly increases the risk of CRC and founder effects have been established. xref , xref , xref "
CK2beta affects ATXN3
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2
CK2alpha affects ATXN3
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2
reach
"Calpeptin (a calpain inhibitor) decreased levels of atxn3 cleaved fragments in atxn3-84Q zebrafish and rescued the motor phenotype, but it also removed all ATXN3 expanded protein due to an increase in autophagic flux (indicated by reduced p62 levels and increased LC3II levels) that cleared autolysosomes."
| PMC
sparser
"Mutations in CAPN5 are associated with the devastating retinal degenerative disease autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). xref xref – xref ADNIV is a hereditary autoimmune disease of the eye that is characterized by abnormal retinal pigmentation, retinal neovascularization, photoreceptor degeneration, vitreous hemorrhage, intraocular fibrosis, and tractional retinal detachment."
sparser
"Best vitelliform macular dystrophy (BVMD) is autosomal dominant juvenile onset maculopathy, which is associated with a mutation in human BEST1 gene.[ xref ] hBEST1 gene encodes bestrophin-1 (Best1) protein, which is expressed basolaterally in retinal pigment epithelium (RPE) [ xref ] and in astrocytes.[ xref ] BVMD involves several stages and leads to loss of central vision."
Atx7 affects ATXN3
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2
Alzheimer Disease affects APP
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2
ATXN3 affects ubiquitin-like domain
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2
ATXN3 affects transcriptional regulator
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2
ATXN3 binds transcriptional regulator. 2 / 2
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2
sparser
"Ataxin-3 normally interacts with numerous transcriptional regulators including the forkhead box O (FOXO)-4 transcription factor, TATA-binding protein-associated factor TAFII130 [ xref ], CBP [ xref ], nuclear co-repressor receptor NCoR [ xref ], histone deacetylases [ xref ], and DNA repair protein RAD23 [ xref ]."
ATXN3 affects superoxide
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2
ATXN3 increases the amount of superoxide. 2 / 2
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2
reach
"Ataxin-3 has been shown to activate transcription factor forkhead box protein O4 (FOXO4) and induce the expression of manganese superoxide dismutase (SOD2), an antioxidant enzyme, under oxidative stress conditions; however, when ataxin-3 is expanded, this transcriptional activation effect is reduced and, in fact, SOD2 levels are decreased in SCA3 patients brain samples ."
sparser
"The autosomal dominant form of STL is caused by mutations in COL2A1 [ xref ], COL11A1 [ xref ], or COL11A2 (Gene ID 1302, OMIM) [ xref ], while the autosomal recessive form of STL is caused by mutations in COL9A1 (Gene ID 12839, OMIM) [ xref ], COL9A2 (Gene ID 1298, OMIM) [ xref ], COL9A3 (Gene ID 1299, OMIM) [ xref ], or LOXL3 (Gene ID 84695, OMIM) [ xref , xref ]."
ATXN3 affects protein degradation
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2
ATXN3 affects polyQ78
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2
ATXN3 affects poly-ubiquitin chains
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2
ATXN3 affects mutation
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2
ATXN3 affects monoubiquitin
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1
1
ATXN3 affects manganese atom
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2
ATXN3 increases the amount of manganese atom. 2 / 2
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2
reach
"Ataxin-3 has been shown to activate transcription factor forkhead box protein O4 (FOXO4) and induce the expression of manganese superoxide dismutase (SOD2), an antioxidant enzyme, under oxidative stress conditions; however, when ataxin-3 is expanded, this transcriptional activation effect is reduced and, in fact, SOD2 levels are decreased in SCA3 patients brain samples ."
ATXN3 affects low-density lipoprotein
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2
ATXN3 affects endogenous DnaJ-1 protein
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2
ATXN3 affects endocrine
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2
ATXN3 affects dynein
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1
ATXN3 affects crystallin
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2
ATXN3 affects calcium(2+)
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2
ATXN3 affects autophagosome
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2
ATXN3 inhibits autophagosome. 2 / 2
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2
eidos
"ATXN3 depletion impairs autophagic degradation of long-lived proteins and increases the number of autophagosomes To explore whether human ATXN3 is involved in autophagy , we analyzed the autophagic flux directly by determining the fraction of long-lived intracellular proteins that were either degraded by basal or starvation-induced autophagy in control or ATXN3-depleted cells ."
ATXN3 affects arginine
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2
ATXN3 affects activity
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2
sparser
"Cowden syndrome (CS), an autosomal dominant disease associated with mutations in the PTEN tumor suppressor gene on chromosome 10q10.22-23, is associated with elevated risks of breast and thyroid cancer, as well as diverse benign neoplasms including gastrointestinal hamartomatous polyps, lipomas, giant fibroadenomas of the breast, hemangiomas, and multiple early-onset uterine leiomyomas [ xref ]."
sparser
"The PEO1 ( C10ORF2 ) mutations are associated with autosomal dominant progressive external ophthalmoplegia (PEO) (PEOA3), parkinsonism, as well as infantileonset spinocerebellar ataxia. xref , xref , xref Biochemical analyses of purified mutant PEO1 proteins have been performed, but the results have been mixed. xref , xref , xref The functional defects of mutant Twinkle proteins have also been studied in the ortholog in Drosophila . xref Transgenic mice carrying a point mutation at amino acid residue 360 (A360T), or a short repeat of amino acids 353 to 365 reproduced histopathology and histochemical changes resulting from mitochondrial respiratory chain dysfunction."
sparser
"TWNK was also associated with autosomal dominant progressive external ophthalmoplegia (adPEO, OMIM #609286) which can result in ophthalmoparesis with exercise intolerance, ataxia, peripheral neuropathy and multiple mtDNA deletions and at least 40 causative mutations for adPEO have been identified up to now [ xref ]."
reach
"Consistent with defective DSB induced ubiquitylation, we found that depletion of ataxin-3 also significantly reduced both BRCA1 (Fig XREF_FIG D) and 53BP1 accumulation (Fig XREF_FIG E) to laser inflicted DNA damage, as well as to ionizing radiation induced foci (XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY)."
reach
"Genes that were part of this signature on the brain side were the TCF4, ATN1, PPP2R2B, ATXN10 and ATXN3, which are associated with neurodegenerative and developmental disorders such as Pitt-Hopkins Syndrome [XREF_BIBR], Dentatorubral pallidoluysian atrophy [XREF_BIBR], SCA12 [XREF_BIBR], SCA10 [XREF_BIBR] and SCA3 [XREF_BIBR]."
reach
"STB/HAP1 can also interact with the causal agents of some other polyQ diseases, such as with Abelson helper integration site 1 in Joubert syndrome (Sheng et al., 2008), ataxin 3 in Machado-Joseph disease (Takeshita et al., 2011) and TATA binding protein in spinocerebellar ataxia type 17 (Prigge and Schmidt, 2007)."
sparser
"There are several DNA tests currently available that are based on dominant or codominant mutations, including the RHO mutation for an autosomal dominant form of PRA in the English Mastiff offered by OptiGen () (Kijas et al. xref ), the mutation in HSF4 that is associated with hereditary cataract in the Australian Shepherd that is offered by the Animal Health Trust () (Mellersh et al. xref , xref ), and the polymorphisms associated with renal dysplasia in multiple breeds that is offered by DoGenes () (Whiteley et al. xref )."
sparser
"Deleterious mutations in RUNX1 (Runt-related transcription factor 1; MIM ID *151385) are associated with a rare Autosomal Dominant hereditary cancer syndrome (linked to 21q22.12) that is characterized by qualitative and quantitative platelet defects with a high-propensity for myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and lymphoid malignancies( xref )."
sparser
"In humans, heterozygous RUNX1 mutation is associated with an autosomal dominant disorder, the familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) (Mendelian Inheritance in Man [MIM] 601399), characterized by impaired megakaryopoiesis, quantitative and qualitative defects in platelet function, and over 40% risk of development of myelodysplastic syndrome (MDS) or AML at a median age of 33 years [ xref – xref ]."
ATXN3 affects Prostatic Neoplasms
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1
1
sparser
" PROM1 (OMIM 612657) codes for a transmembrane glycoprotein (Prominin-1) that localizes to the base of the rod and cone outer segments and is involved in disc assembly and maintenance of outer segment structure. xref PROM1 is associated with both autosomal dominant (AD) xref , xref and AR xref retinal dystrophies, with the AD forms tending to be later onset and milder. xref PROM1 is responsible for between 1.0% and 9.5% of AR CRD (arCRD) cases. xref , xref , xref "
sparser
"PNKP has been shown to promote transcription-coupled double-strand break repair ( xref ) and often performs transcription-coupled repair when in complex with huntingtin protein, RNA polymerase II subunit A, ataxin-3, and cyclic AMP-response element binding protein (CBP) ( xref )."
sparser
"The mechanisms for this were recently suggested to be through direct interactions between HTT and RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP) [ xref ], as well as complexes with the DNA double-strand break repair complex Ku70/Ku80 [ xref ]."
ATXN3 affects PLD
|
2
sparser
"Furthermore, the altered pitx2 expression pattern, together with the described morphological features of the lens-ablated fish suggests that Astyanax mexicanus could be considered as an alternative teleost model organism in which to study Axenfeld-Rieger syndrome (ARS), a rare autosomal dominant developmental disorder that is associated with PITX2 and which has both ocular and non-ocular abnormalities."
sparser
"The list of the diseases associated with OPLL includes hypophosphatemic rickets/osteomalacia, including an autosomal dominant form (MIM 193100) caused by FGF23 mutations, an X-linked dominant form (MIM 307800) caused by PHEX mutations, an X-linked recessive form (MIM 300554) caused by CLCN5 mutations, and autosomal recessive forms caused by DMP1 (MIM 600980) and ENPP1 (MIM 173335) mutations."
sparser
"Several forms of hypophosphatemic rickets are known, including an X-linked form (MIM 307800) caused by phosphate regulating endopeptidase homolog, X-linked ( PHEX ) mutations (MIM 300550), an autosomal dominant form (MIM 193100) caused by fibroblast growth factor 23 ( FGF23 ) mutations (MIM 605380), an X-linked recessive form (MIM 300554) caused by chloride channel, voltage-sensitive 5 ( CLCN5 ) mutations (MIM 300008), and autosomal recessive forms caused by dentin matrix acidic phosphoprotein 1 ( DMP1 ) (MIM 600980), hypophosphatemic rickets, autosomal recessive 2 ( ARHR2 ) (MIM 613312) or ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) (MIM 173335) mutations. 'tiptoe walking' ( TTW ) mouse, which has a spontaneous nonsense mutation in ENPP1 is a good model for OPLL.[ xref ] Also, OPPL is a frequent complication in patients with endocrine disorders including hypoparathyroidism[ xref ] and acromegaly/gigantism.[ xref ] However, most cases of OPLL are idiopathic."
ATXN3 affects PCSK9, and low-density lipoprotein
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2
ATXN3 affects Neoplasm Invasiveness
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1
1
ATXN3 activates Neoplasm Invasiveness. 2 / 2
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1
1
sparser
"For example, causal variants in the MUC1 gene, which is associated with autosomal dominant tubulointerstitial kidney disease (ADTKD- MUC1 ; OMIM 174000) and contains a highly repetitive, GC-rich sequence, were missed by NGS-based regional capture, WES, and WGS and were identified only by long-range PCR and molecular cloning xref ."
sparser
"Initial translational efforts might, therefore, be more successful in disorders with more homogeneous underlying pathology, such as the primary tauopathies, progressive supranuclear palsy (PSP) and autosomal dominant frontotemporal lobar degeneration (FTLD) associated with MAPT mutations, in all of which tau is the major abnormal protein."
sparser
"FPLD (MIM 151660) is a rare autosomal dominant form of insulin resistance caused by mutant LMNA, which encodes nuclear lamin A/C, a structural component of the nuclear envelope.[ xref ] FPLD is characterized by loss of fat affecting the limbs and trunk, accumulation of fat in the neck and face, and predisposition to insulin resistance, leading to complications such as glucose intolerance, dyslipidemia, high blood pressure, liver steatosis, and increased risk for coronary heart disease."
ATXN3 affects LC3C
|
2
ATXN3 affects LC3-II
|
2
ATXN3 affects IFN-I
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2
sparser
"PNKP has been shown to promote transcription-coupled double-strand break repair ( xref ) and often performs transcription-coupled repair when in complex with huntingtin protein, RNA polymerase II subunit A, ataxin-3, and cyclic AMP-response element binding protein (CBP) ( xref )."
sparser
"The mechanisms for this were recently suggested to be through direct interactions between HTT and RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP) [ xref ], as well as complexes with the DNA double-strand break repair complex Ku70/Ku80 [ xref ]."
ATXN3 affects HHR23
|
2
sparser
"Finally, mutations causing the autosomal dominant form of dopa-responsive dystonia have been identified in the gene coding for GTP cyclohydrolase I. Mutations in tyrosine hydroxylase have been identified in two brothers and put forward as evidence of an autosomal recessive form of the disease."
reach
"These findings suggest that anti-NP response at an early stage effectively controls infection and contributes to cross-protective immunity.A single immunization with ML29 fully protected guinea pigs and marmosets against fatal disease caused by LASV/JOS (lineage IV) and Nigerian strain 803213 (lineage II)46,88."
reach
"Expansion of polyQ domains in huntingtin and the deubiquitinase ataxin-3 causes Huntington’s disease characterized by loss of striatal neurons and hence changes in mood and personality, defective motor coordination, and involuntary movements and type-3 spinocerebellar ataxia (SCA3), a form of neurodegeneration in the striatum and cerebellum, respectively [104]."
| PMC
ATXN3 affects DSBs
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2
sparser
"Germline mutations in DICER1 are associated with an autosomal dominant hereditary cancer predisposition syndrome that confers an increased risk for the development of several rare childhood and adult-onset tumors, the most frequent of which include pleuropulmonary blastoma, ovarian sex cord-stromal tumors, cystic nephroma, and thyroid gland neoplasia."
sparser
"Mutations in human CRX (NCBI Reference Sequence: NG_008605.1) have been associated with autosomal dominant forms of the retinal degenerative diseases Retinitis Pigmentosa (adRP), Cone-Rod Dystrophy (adCoRD) and Leber Congenital Amaurosis (adLCA), with different ages of onset and severity xref xref – xref ."
sparser
"Lynch syndrome (LS) or hereditary non-polyposis colorectal cancer, is an autosomal dominant form of CRC that may account for up to 5% of all CRC cases. xref The penetrance for development of malignancy is up to 68.7% in males and 52% in females. xref Founder effects for LS have been discovered in several populations, including Newfoundland, Canada. xref It is believed that the increased rates of CRC in this province, which are among the highest in the world, may be attributable to a high rate of familial cancer in the population and possibly to the presence of novel susceptibility genes. xref , xref Familial adenomatous polyposis is another autosomal dominant inherited syndrome that greatly increases the risk of CRC and founder effects have been established. xref , xref , xref "
ATXN3 affects CK2beta
|
2
ATXN3 affects CK2alpha
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2
sparser
"Mutations in CAPN5 are associated with the devastating retinal degenerative disease autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). xref xref – xref ADNIV is a hereditary autoimmune disease of the eye that is characterized by abnormal retinal pigmentation, retinal neovascularization, photoreceptor degeneration, vitreous hemorrhage, intraocular fibrosis, and tractional retinal detachment."
sparser
"Best vitelliform macular dystrophy (BVMD) is autosomal dominant juvenile onset maculopathy, which is associated with a mutation in human BEST1 gene.[ xref ] hBEST1 gene encodes bestrophin-1 (Best1) protein, which is expressed basolaterally in retinal pigment epithelium (RPE) [ xref ] and in astrocytes.[ xref ] BVMD involves several stages and leads to loss of central vision."
reach
"STB/HAP1 can also interact with the causal agents of some other polyQ diseases, such as with Abelson helper integration site 1 in Joubert syndrome (Sheng et al., 2008), ataxin 3 in Machado-Joseph disease (Takeshita et al., 2011) and TATA binding protein in spinocerebellar ataxia type 17 (Prigge and Schmidt, 2007)."
APP affects Alzheimer Disease
|
2
APP affects AD
|
2
reach
"STB/HAP1 can also interact with the causal agents of some other polyQ diseases, such as with Abelson helper integration site 1 in Joubert syndrome (Sheng et al., 2008), ataxin 3 in Machado-Joseph disease (Takeshita et al., 2011) and TATA binding protein in spinocerebellar ataxia type 17 (Prigge and Schmidt, 2007)."
sparser
"The list of the diseases associated with OPLL includes hypophosphatemic rickets/osteomalacia, including an autosomal dominant form (MIM 193100) caused by FGF23 mutations, an X-linked dominant form (MIM 307800) caused by PHEX mutations, an X-linked recessive form (MIM 300554) caused by CLCN5 mutations, and autosomal recessive forms caused by DMP1 (MIM 600980) and ENPP1 (MIM 173335) mutations."
sparser
"Several forms of hypophosphatemic rickets are known, including an X-linked form (MIM 307800) caused by phosphate regulating endopeptidase homolog, X-linked ( PHEX ) mutations (MIM 300550), an autosomal dominant form (MIM 193100) caused by fibroblast growth factor 23 ( FGF23 ) mutations (MIM 605380), an X-linked recessive form (MIM 300554) caused by chloride channel, voltage-sensitive 5 ( CLCN5 ) mutations (MIM 300008), and autosomal recessive forms caused by dentin matrix acidic phosphoprotein 1 ( DMP1 ) (MIM 600980), hypophosphatemic rickets, autosomal recessive 2 ( ARHR2 ) (MIM 613312) or ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) (MIM 173335) mutations. 'tiptoe walking' ( TTW ) mouse, which has a spontaneous nonsense mutation in ENPP1 is a good model for OPLL.[ xref ] Also, OPPL is a frequent complication in patients with endocrine disorders including hypoparathyroidism[ xref ] and acromegaly/gigantism.[ xref ] However, most cases of OPLL are idiopathic."
AM146 affects ATXN3
|
2