DOI: 10.1042/bst0360105. Roles of VCP in human neurodegenerative disorders

Roles of VCP in human neurodegenerative disorders

10.1042/bst0360105

Crossref journal-article

Portland Press Ltd.

Biochemical Society Transactions (288)

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.

Bibliography

Kakizuka, A. (2008). Roles of VCP in human neurodegenerative disorders. Biochemical Society Transactions, 36(1), 105â108.

Authors 1

Akira Kakizuka (first)

References 20 Referenced 57

10.1038/ng1194-221 / Nat. Genet. / CAG expansions in a novel gene for Machado–Joseph disease at chromosome 14q32.1 by Kawaguchi (1994)
10.1016/S0168-9525(98)01559-5 / Trends Genet. / Protein precipitation: a common etiology in neurodegenerative disorders? by Kakizuka (1998)
10.1080/1521654032000114339 / IUBMB Life / Polyglutamine diseases and molecular chaperones by Kimura (2003)
10.1038/ng0696-196 / Nat. Genet. / Expanded poly-glutamine in the Machado–Joseph disease protein induces cell death in vitro and in vivo by Ikeda (1996)
10.1046/j.1365-2443.1999.00294.x / Genes Cells / Triggering of neuronal cell death by accumulation of activated SEK1 on nuclear polyglutamine aggregations in PML bodies by Yasuda (1999)
10.1159/000072862 / Cytogenet. Genome Res. / Molecular analyses of Machado–Joseph disease by Kobayashi (2003)
10.1038/sj.cdd.4400907 / Cell Death Differ. / VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegeneration by Hirabayashi (2001)
10.1074/jbc.M207783200 / J. Biol. Chem. / Functional ATPase activity of p97/VCP is required for the quality control of endoplasmic reticulum in neuronally differentiated mammalian PC12 cells by Kobayashi (2002)
10.1038/sj.cdd.4400955 / Cell Death Differ. / Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegenerations in Drosophila by Higashiyama (2002)
10.1038/sj.emboj.7601043 / EMBO J. / An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis by Boeddrich (2006)
10.1016/S0304-3940(03)00280-5 / Neurosci. Lett. / Vacuole-creating protein in neurodegenerative diseases by Mizuno (2003)
10.1074/jbc.M406683200 / J. Biol. Chem. / Physical and functional interaction between dorfin and valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders by Ishigaki (2004)
10.1111/j.1365-2443.2007.01099.x / Genes Cells / Involvement of valosin-containing protein (VCP)/p97 in the formation and clearance of abnormal protein aggregates by Kobayashi (2007)
10.1016/j.febslet.2005.12.044 / FEBS Lett. / Dominant-negative effect of mutant valosin-containing protein in aggresome formation by Kitami (2006)
10.1038/ng1332 / Nat. Genet. / Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein by Watts (2004)
10.1212/01.wnl.0000180407.15369.92 / Neurology / Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene by Haubenberger (2005)
10.1097/00005072-200606000-00005 / J. Neuropathol. Exp. Neurol. / Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations by Forman (2006)
10.1016/0960-8966(93)90021-B / Neuromuscul. Disord. / Ubiquitin and β-amyloid-protein in inclusion body myositis (IBM), familial IBM-like disorder and oculopharyngeal muscular dystrophy: an immunocytochemical study by Leclerc (1993)
10.1007/BF00294807 / Acta Neuropathol. / Tau protein immunoreactivity in muscle fibers with rimmed vacuoles differs from that in regenerating muscle fibers by Murakami (1995)
10.1093/jnen/59.7.592 / J. Neuropathol. Exp. Neurol. / Novel immunolocalization of α-synuclein in human muscle of inclusion-body myositis, regenerating and necrotic muscle fibers, and at neuromuscular junctions by Askanas (2000)

Dates

Type	When
Created	17 years, 5 months ago (March 17, 2008, 2:25 p.m.)
Deposited	3 years, 9 months ago (Nov. 18, 2021, 5:59 p.m.)
Indexed	2 months, 4 weeks ago (June 6, 2025, 1:29 p.m.)
Issued	17 years, 7 months ago (Jan. 22, 2008)
Published	17 years, 7 months ago (Jan. 22, 2008)
Published Online	17 years, 7 months ago (Jan. 22, 2008)
Published Print	17 years, 7 months ago (Feb. 1, 2008)

Funders 0

None

BibTeX

@article{Kakizuka_2008, title={Roles of VCP in human neurodegenerative disorders}, volume={36}, ISSN={1470-8752}, url={http://dx.doi.org/10.1042/bst0360105}, DOI={10.1042/bst0360105}, number={1}, journal={Biochemical Society Transactions}, publisher={Portland Press Ltd.}, author={Kakizuka, Akira}, year={2008}, month=jan, pages={105–108} }

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