Genetic ablation and chemical inhibition of IP3R1 reduce mutant huntingtin aggregation

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• 作者：Peter O.  ; Bauer^a ; Roman  ; Hudec^b ; Shoichiro  ; Ozaki^b ; Misako  ; Okuno^a ; Etsuko  ; Ebisui^b ; Katsuhiko  ; Mikoshiba^b ;   ; ^c ; Nobuyuki  ; Nukina^a ;   ; ^{nukina@brain.riken.jp}
• 关键词：Huntington&rsquo ; s disease ; Huntingtin ; Polyglutamine ; IP3R1 ; 2-APB ; shRNA
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2011
• 出版时间：9 December 2011
• 年：2011
• 卷：416
• 期：1-2
• 页码：13-17
• 全文大小：479 K

文摘

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 Ca²⁺ release (IICR). Their effect on aggregation was not correlated with the store-operated Ca²⁺ 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.