IndraLab

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Mutated ATXN3 activates ATM. 9 / 9
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"Knockdown of normal ATXN3 or PNKP, or expression of mutant ATXN3 increased the accumulation of DNA damage and persistent activation of the ATM and p53 dependent DNA repair pathway, suggesting ATXN3 may be a key regulator of PNKP dependent DNA repair."
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"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)."
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"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.."
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"To investigate whether mutant ATXN3 activates ATM signaling in SCA3, we expressed ATXN3-Q84 in differentiated SH-SY5Y cells and assessed activation of the ATM pathway."
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"Since oxidative stress alone can activate the ATM pathway [XREF_BIBR], we sought to determine whether mutant ATXN3 activates ATM via an oxidation dependent mechanism."
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"These data substantiate our previous interpretation that mutant ATXN3 activates the p53 dependent pro death pathway by activating ATM, and that chronic activation of the ATM --> p53 pathway plays a pivotal role in mediating neuronal death in SCA3."
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"Consistent with these reports, our data show that mutant ATXN3 mediated activation of ATM --> c-Abl pathway enhanced the phosphorylation and facilitated the nuclear translocation of PKCdelta in cells, and in SCA3 transgenic mouse brains."
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"Mutant ATXN3 activates the pro apoptotic p53 pathway by activating ATM in SCA3."
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"Likewise, expression of the mutant ATXN3 carrying 72 and 80 poly-glutamines (ATXN3-Q72 and ATXN3-Q80) in SH-SY5Y cells also strongly activated the DNA damage response ATM pathway (XREF_SUPPLEMENTARY)."
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