Research article
ROCK-phosphorylated vimentin modifies mutant huntingtin aggregation via sequestration of IRBIT
- † Equal contributors
1 Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
2 Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
3 Calcium Oscillation Project, ICORP-SORST, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
4 Present address: Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA
5 Present address: Institute of Biochemistry, Nutrition and Health Protection, Department of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 812 37, Bratislava, Slovakia
Molecular Neurodegeneration 2012, 7:43 doi:10.1186/1750-1326-7-43
Published: 28 August 2012Abstract
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.
