Roles of VCP in human neurodegenerative disorders
- 22 January 2008
- journal article
- Published by Portland Press Ltd. in Biochemical Society Transactions
- Vol. 36 (1), 105-108
- https://doi.org/10.1042/bst0360105
Abstract
Abnormal protein aggregates are commonly observed in affected neurons in many neurodegenerative disorders. We have reported that VCP (valosin-containing protein) co-localizes with protein aggregates in neurons of patients and in cultured cells expressing diseased proteins. However, the significance of such co-localization remains to be elucidated. In the present paper, I discuss the involvement of VCP in the processes of both the formation and re-solubilization of abnormal protein aggregates. In the study, VCP recognized and accumulated on to pre-formed protein aggregates created by proteasome inhibition. VCP knockdown or expression of dominant-negative VCP both significantly delayed the elimination of ubiquitin-positive aggregates. VCP was also involved in the clearance of pre-formed polyglutamine aggregates. Paradoxically, VCP knockdown also diminished polyglutamine aggregate formation. Furthermore, its ATPase activity is required for the re-solubilization and reactivation of heat-denatured proteins, such as luciferase, from insoluble aggregates. We thus propose that VCP functions as a mediator for both aggregate formation and clearance, depending on the concentration of soluble aggregate-prone proteins, indicating that VCP has dual functions as an aggregate formase and an unfoldase. We then examined the potentially elevated aggregate formase activities of mutant VCPs, which have been found to cause IBMPFD (inclusion body myopathy, Paget disease of bone and front-temporal dementia). Indeed, all IBMPFD VCPs showed elevated aggregate formase activities on both polyglutamine and proteasome inhibitor-mediated aggregates. Biochemically, all IBMPFD VCPs showed elevated ATPase activities as well as elevated binding affinities not only for several VCP cofactors, but also for ubiquitinated proteins. Thus controlling the function of VCP, namely decreasing aggregate formase activities and/or increasing unfoldase activities, is expected to be of great benefit for the treatment of IBMPFD and also several neurodegenerative disorders with intracellular protein inclusions.Keywords
This publication has 20 references indexed in Scilit:
- An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesisThe EMBO Journal, 2006
- Molecular analyses of Machado-Joseph diseaseCytogenetic and Genome Research, 2003
- Polyglutamine Diseases and Molecular ChaperonesIUBMB Life, 2003
- Functional ATPase Activity of p97/Valosin-containing Protein (VCP) Is Required for the Quality Control of Endoplasmic Reticulum in Neuronally Differentiated Mammalian PC12 CellsPublished by Elsevier BV ,2002
- Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegenerationCell Death & Differentiation, 2002
- VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegenerationCell Death & Differentiation, 2001
- Triggering of neuronal cell death by accumulation of activated SEK1 on nuclear polyglutamine aggregations in PML bodiesGenes to Cells, 1999
- Protein precipitation: a common etiology in neurodegenerative disorders?Trends in Genetics, 1998
- Expanded polyglutamine in the Machado–Joseph disease protein induces cell death in vitro and in vivoNature Genetics, 1996
- CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1Nature Genetics, 1994