ROCK-phosphorylated vimentin modifies mutant huntingtin aggregation via sequestration of IRBIT.
ROCK-phosphorylated vimentin modifies mutant huntingtin aggregation via sequestration of IRBIT.
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DOI：
10.1186/1750-1326-7-43
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发表时间：
2012-08-28
影响因子：
15.1
通讯作者：
Nukina N
中科院分区：
文献类型：
--
作者：
Bauer PO;Hudec R;Goswami A;Kurosawa M;Matsumoto G;Mikoshiba K;Nukina N
亨廷顿氏病（HD）是一种致死性遗传性神经退行性疾病，由含有扩展的多聚谷氨酰胺（polyQ）束的突变亨廷顿蛋白（Htt）积累引起。激活负责肌醇诱导的Ca 2+从内质网（ER）释放的通道，被发现在很大程度上有助于HD的神经变性。重要的是，已显示1型肌醇1，4，5-三磷酸（IP 3）受体（IP 3R 1）的化学和遗传抑制减少突变型Htt聚集。在这项研究中，我们提出了一种新的调节机制，IP 3 R1活性的III型中间丝波形蛋白隔离的负调节IP 3 R1，伊尔比特，到核周包涵体，并减少其与IP 3 R1的相互作用，从而促进突变体Htt聚集。蛋白酶体抑制剂MG 132可引起polyQ蛋白的聚集和聚集，增强了伊尔比特的螯合作用。此外，我们发现，伊尔比特螯合可以防止rho激酶抑制剂，Y-27632。我们的研究结果表明，波形蛋白是治疗polyQ疾病的一个新的和额外的目标。
Huntington's Disease (HD) is a fatal hereditary neurodegenerative disease caused by the accumulation of mutant huntingtin protein (Htt) containing an expanded polyglutamine (polyQ) tract. Activation of the channel responsible for the inositol-induced Ca2+ release from ensoplasmic reticulum (ER), was found to contribute substantially to neurodegeneration in HD. Importantly, chemical and genetic inhibition of inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1) has been shown to reduce mutant Htt aggregation. In this study, we propose a novel regulatory mechanism of IP3R1 activity by type III intermediate filament vimentin which sequesters the negative regulator of IP3R1, IRBIT, into perinuclear inclusions, and reduces its interaction with IP3R1 resulting in promotion of mutant Htt aggregation. Proteasome inhibitor MG132, which causes polyQ proteins accumulation and aggregation, enhanced the sequestration of IRBIT. Furthermore we found that IRBIT sequestration can be prevented by a rho kinase inhibitor, Y-27632. Our results suggest that vimentin represents a novel and additional target for the therapy of polyQ diseases.
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DOI：
10.1083/jcb.143.7.1883
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Johnston JA;Ward CL;Kopito RR
通讯作者：
Kopito RR
影响因子：
3.7
作者：
Deyts C;Galan-Rodriguez B;Martin E;Bouveyron N;Roze E;Charvin D;Caboche J;Bétuing S
通讯作者：
Bétuing S
DOI：
10.1083/jcb.81.3.570
发表时间：
1979-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Franke WW;Schmid E;Osborn M;Weber K
通讯作者：
Weber K
影响因子：
2.7
作者：
BIGNAMI, A;RAJU, T;DAHL, D
通讯作者：
DAHL, D
影响因子：
3.7
作者：
FRANKE, WW;SCHMID, E;WEBER, K
通讯作者：
WEBER, K