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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2012

Open Access 01-12-2012 | Research article

ROCK-phosphorylated vimentin modifies mutant huntingtin aggregation via sequestration of IRBIT

Authors: Peter O Bauer, Roman Hudec, Anand Goswami, Masaru Kurosawa, Gen Matsumoto, Katsuhiko Mikoshiba, Nobuyuki Nukina

Published in: Molecular Neurodegeneration | Issue 1/2012

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Abstract

Background

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.

Results

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.

Conclusions

Our results suggest that vimentin represents a novel and additional target for the therapy of polyQ diseases.
Appendix
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Metadata
Title
ROCK-phosphorylated vimentin modifies mutant huntingtin aggregation via sequestration of IRBIT
Authors
Peter O Bauer
Roman Hudec
Anand Goswami
Masaru Kurosawa
Gen Matsumoto
Katsuhiko Mikoshiba
Nobuyuki Nukina
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2012
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/1750-1326-7-43

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