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, Ming Guo

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere17834
JournaleLife
Volume6
DOIs
StatePublished - Mar 21 2017

Fingerprint

Frontotemporal Dementia
Muscular Diseases
Inclusion Bodies
Defects
Mitochondrial Dynamics
Drosophila
Muscle
CDC48 protein
Fusion reactions
Muscles
Membrane Fusion
Mitochondrial Membranes
Pathology
Cell death
Missense Mutation
Fibroblasts
Neurodegenerative Diseases
Muscle Cells
Cell Death
Alleles

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Valosin-containing protein (VCP/p97) inhibitors relieve mitofusin-dependent mitochondrial defects due to VCP disease mutants. / Zhang, Ting; Mishra, Prashant; Hay, Bruce A.; Chan, David; Guo, Ming.

In: eLife, Vol. 6, e17834, 21.03.2017.

Research output: Contribution to journalArticle

@article{eb107d1dd9d24af08daf1c319c525a3c,
title = "Valosin-containing protein (VCP/p97) inhibitors relieve mitofusin-dependent mitochondrial defects due to VCP disease mutants",
abstract = "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.",
author = "Ting Zhang and Prashant Mishra and Hay, {Bruce A.} and David Chan and Ming Guo",
year = "2017",
month = "3",
day = "21",
doi = "10.7554/eLife.17834",
language = "English (US)",
volume = "6",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Valosin-containing protein (VCP/p97) inhibitors relieve mitofusin-dependent mitochondrial defects due to VCP disease mutants

AU - Zhang, Ting

AU - Mishra, Prashant

AU - Hay, Bruce A.

AU - Chan, David

AU - Guo, Ming

PY - 2017/3/21

Y1 - 2017/3/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85015917793&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85015917793&partnerID=8YFLogxK

U2 - 10.7554/eLife.17834

DO - 10.7554/eLife.17834

M3 - Article

C2 - 28322724

AN - SCOPUS:85015917793

VL - 6

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e17834

ER -