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Valosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants

Zhang, Ting and Mishra, Prashant and Hay, Bruce A. and Chan, David and Guo, Ming (2017) Valosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants. eLife, 6 . Art. No. e17834. ISSN 2050-084X. PMCID PMC5360448. doi:10.7554/eLife.17834.

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Missense mutations of valosin-containing protein (VCP) cause an autosomal dominant disease known as inclusion body myopathy, Paget disease with frontotemporal dementia (IBMPFD) and other neurodegenerative disorders. The pathological mechanism of IBMPFD is not clear and there is no treatment. We show that endogenous VCP negatively regulates Mitofusin, which is required for outer mitochondrial membrane fusion. Because 90% of IBMPFD patients have myopathy, we generated an in vivo IBMPFD model in adult Drosophila muscle, which recapitulates disease pathologies. We show that common VCP disease mutants act as hyperactive alleles with respect to regulation of Mitofusin. Importantly, VCP inhibitors suppress mitochondrial defects, muscle tissue damage and cell death associated with IBMPFD models in Drosophila. These inhibitors also suppress mitochondrial fusion and respiratory defects in IBMPFD patient fibroblasts. These results suggest that VCP disease mutants cause IBMPFD through a gain-of-function mechanism, and that VCP inhibitors have therapeutic value.

Item Type:Article
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URLURL TypeDescription CentralArticle
Chan, David0000-0002-0191-2154
Additional Information:© 2017 Zhang et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 15 May 2016; Accepted: 13 February 2017; Published: 21 March 2017. We are grateful to the support of the Natalie R and Eugene S Jones Fund in Aging and Neurode-generative Disease Research. We would like to thank Hansong Deng for first noting the suppression of PINK1 mutant phenotype by VCP overexpression, Dr. Tzu Kang Sang from the National Tsing Hua University, Taiwan, for the VCP disease mutants allele flies, Dr. Hugo Bellen from the Baylor College of Medicine for the kind gift of pCasper-Mfn-HA flies, Dr. CK Yao from Academia Sinica, Taipei, for pCasper-Mfn-eGFP construct and Dr. Frank A Laski for the microtome usage. Author contributions: TZ, PM, BAH, Conceptualization, Methodology, Writing—original draft, Writing—review and editing; DC, Conceptualization, Supervision, Data curation, Formal analysis, Writing—original draft, Writing—review and editing; MG, Conceptualization, Supervision, Funding acquisition, Data curation, Formal analysis, Methodology, Writing—original draft, Writing—review and editing. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The authors declare that no competing interests exist.
Funding AgencyGrant Number
Ellison Medical FoundationUNSPECIFIED
McKnight Endowment Fund for NeuroscienceUNSPECIFIED
Glenn Family FoundationUNSPECIFIED
Natalie R. and Eugene S. Jones Fund in Aging and Neurodegenerative Disease ResearchUNSPECIFIED
PubMed Central ID:PMC5360448
Record Number:CaltechAUTHORS:20170327-104810282
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Official Citation:Valosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants Ting Zhang, Prashant Mishra, Bruce A Hay, David Chan, and Ming Guo eLife 2017;6:e17834
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75413
Deposited By: Tony Diaz
Deposited On:27 Mar 2017 18:55
Last Modified:15 Nov 2021 16:33

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