IndraLab

Statements

CACNA1A activates translation. 12 / 12
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"To examine the therapeutic effects of miR-3191-5p-mediated reduction of CACNA1A IRES driven alpha1ACT SCA6 translation on the disease phenotype of SCA6 mice, we constructed an AAV9 vector that allowed for the simultaneous expression of GFP and either miR-3191-5p (AAV9-miR-3191-5p) or a nonspecific mock miRNA (AAV9-miR-mock) (XREF_SUPPLEMENTARY)."
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"Identification of eIF4AII, which may provide helicase activity, and eIF4GII, which may serve as a scaffold, in the mechanism of CACNA1A IRES mediated translation supports recent findings that show the effect of eIFs on cellular IRESs in human disease."
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"Because both eIF4AII and eIF4GII affected not only CACNA1A IRES driven translation of alpha1ACT but also cap dependent translation of full-length alpha1A (XREF_FIG), we used IRES-alpha1ACT vectors (XREF_SUPPLEMENTARY) to test the binding affinities of eIF4AII and eIF4GII to CACNA1A IRES."
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"We identified miR-3191-5p as a microRNA (miRNA) that targeted CACNA1A IRES and preferentially inhibited the CACNA1A IRES driven translation of alpha1ACT in an Argonaute 4 (Ago4)-dependent manner."
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"miR-3191-5p inhibits the CACNA1A IRES driven translation of alpha1ACT while sparing alpha1A and CACNA1A mRNA expression."
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"Although AAV9 mediated intervention with miR-3191-5p did not regulate all of the predicted mRNA targets in our mouse model, we showed that miR-3191-5p has a selective silencing effect on the CACNA1A IRES driven translation of alpha1ACT SCA6 in mice."
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"To examine the effects of these miRNAs on CACNA1A IRES driven translation, we cotransfected these miRNAs with either a bicistronic reporter vector bearing CACNA1A IRES or a control vector into human embryonic kidney (HEK) 293 cells (XREF_FIG)."
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"These results suggest that miR-3191-5p interacts with CACNA1A IRES only through its predicted binding site and inhibits the CACNA1A IRES driven translation of alpha1ACT while sparing alpha1A expression and CACNA1A mRNA expression."
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"These results suggest that miR-3191-5p bound to Ago4 directly interacts with the CACNA1A IRES and selectively inhibits the CACNA1A IRES driven alpha1ACT translation."
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"We also found that knockdown of eIF4GII had a greater effect on the down-regulation of CACNA1A IRES driven alpha1ACT translation than did knockdown of eIF4AII (XREF_FIG)."
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"Considering that an ~ 50% decrease in the number of Purkinje cells is sufficient to cause ataxia and motor deficits in our mouse model, miRNA mediated alpha1ACT SCA6 silencing by blockade of CACNA1A IRES driven translation in greater than half of Purkinje cells would have great potential benefit in presymptomatic or symptomatic SCA6 patients."
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"Because both eukaryotic initiation factors (eIFs) eIF4A and eIF4G have been previously shown to be involved in IRES dependent translation in several types of viral IRESs, we examined the effects of these on CACNA1A IRES driven alpha1ACT translation."
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