| First Author | Bauer PO | Year | 2011 |
| Journal | Biochem Biophys Res Commun | Volume | 416 |
| Issue | 1-2 | Pages | 13-7 |
| PubMed ID | 22056561 | Mgi Jnum | J:179211 |
| Mgi Id | MGI:5301465 | Doi | 10.1016/j.bbrc.2011.10.096 |
| Citation | Bauer PO, et al. (2011) Genetic ablation and chemical inhibition of IP3R1 reduce mutant huntingtin aggregation. Biochem Biophys Res Commun 416(1-2):13-7 |
| abstractText | Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expansion of the polyglutamine (polyQ) stretch in huntingtin (htt). Previously, it has been shown that inhibition of the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) activity reduced aggregation of pathogenic polyQ proteins. Experimentally, this effect was achieved by modification of the intracellular IP3 levels or by application of IP3R1 inhibitors, such as 2-aminoethyl diphenylborinate (2-APB). Unfortunately, there are certain concerns about the 2-APB specificity and cytotoxicity. Moreover, a direct link between IP3R1 and polyQ aggregation has not been shown yet. In this study we show, that down-regulation of the IP3R1 levels by shRNA reduced the aggregation of mutant htt. We tested 2-APB analogs in an attempt to identify less toxic and more IP3R1-specific compounds and found that the effect of these analogs on the reduction of the mutant htt aggregation did weakly correlate with their inhibitory action toward the IP3-induced Ca(2+) release (IICR). Their effect on aggregation was not correlated with the store-operated Ca(2+) entry (SOCE), which is another target of the 2-APB related compounds. Our findings suggest that besides functional contribution of the IP3R inhibition on the mutant htt aggregation there are additional mechanisms for the anti-aggregation effect of the 2-APB related compounds. |
