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Nat Commun. 2016 Aug 26;7:12646. doi: 10.1038/ncomms12646.

VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington's disease.

Author information

1
Department of Physiology &Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
2
Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
3
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
4
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94043, USA.
5
Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
6
Center for Mitochondrial Disease, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.

Abstract

Mutant Huntingtin (mtHtt) causes neurodegeneration in Huntington's disease (HD) by evoking defects in the mitochondria, but the underlying mechanisms remains elusive. Our proteomic analysis identifies valosin-containing protein (VCP) as an mtHtt-binding protein on the mitochondria. Here we show that VCP is selectively translocated to the mitochondria, where it is bound to mtHtt in various HD models. Mitochondria-accumulated VCP elicits excessive mitophagy, causing neuronal cell death. Blocking mtHtt/VCP mitochondrial interaction with a peptide, HV-3, abolishes VCP translocation to the mitochondria, corrects excessive mitophagy and reduces cell death in HD mouse- and patient-derived cells and HD transgenic mouse brains. Treatment with HV-3 reduces behavioural and neuropathological phenotypes of HD in both fragment- and full-length mtHtt transgenic mice. Our findings demonstrate a causal role of mtHtt-induced VCP mitochondrial accumulation in HD pathogenesis and suggest that the peptide HV-3 might be a useful tool for developing new therapeutics to treat HD.

PMID:
27561680
PMCID:
PMC5007466
DOI:
10.1038/ncomms12646
[Indexed for MEDLINE]
Free PMC Article

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