Roles of VCP in human neurodegenerative disorders
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.
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VCP/p97/Cdc48 is involved in DNA replication and repair, cell cycle regulation, and protein clearance.
“VCP/p97/Cdc48 (valosin containing protein) is involved in a wide range of essential cellular processes, including DNA replication and repair, cell cycle regulation, and protein clearance [238,239].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [239]
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“replication and repair, cell cycle regulation, and protein clearance [238,239].”
Background
- Authors
- Kakizuka, A.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Kakizuka, Akira
- ORCID
- Kakizuka, Akira
- Venue
- Biochemical Society Transactions
- Publisher
- Portland Press Ltd.
- Published
- 2008-01-22
- Volume
- 36
- Issue
- 1
- Pages
- 105-108
- ISSN
- 0300-5127 (ISSN-L)
- 1470-8752
- OpenAlex
- W1999001130
- Cited by
- 64
- References
- 20
- Citations by year
- 2025: 4 · 2023: 3 · 2022: 2 · 2021: 8 · 2020: 2 · 2018: 4 · 2016: 3 · 2015: 4 · 2014: 4 · 2013: 1 · 2012: 7
- FWCI
- 3.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Society Transactions (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- VCP, neurodegenerative diseases, protein aggregates, aggregate clearance, polyglutamine aggregates, proteasome inhibition, ubiquitin, ATPase activity, protein solubilization
- MeSH terms
- Valosin Containing Protein, Adenosine Triphosphatases, Humans, Luciferases, Protein Binding, Protein Denaturation, Cell Cycle Proteins, Molecular Chaperones, Neurodegenerative Diseases
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