title: Genetic ablation and chemical inhibition of IP3R1 reduce mutant huntingtin aggregation.
abstract: 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.
authors: Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors: Peter O
authors: PO
authors: Bauer
authors: Roman
authors: R
authors: Hudec
authors: Shoichiro
authors: S
authors: Ozaki
authors: Misako
authors: M
authors: Okuno
authors: Etsuko
authors: E
authors: Ebisui
authors: Katsuhiko
authors: K
authors: Mikoshiba
authors: Nobuyuki
authors: N
authors: Nukina
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D055785:Gene Knockdown Techniques; D000071058:Huntingtin Protein; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D054852:Small Molecule Libraries
chemical_list: C538758:2-aminoethyl diphenylborinate; D001896:Boron Compounds; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; C097188:polyglutamine