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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Apoptosis / drug effects
  • Behavior, Animal
  • Cell Line
  • Corpus Striatum / cytology
  • Corpus Striatum / pathology
  • Disease Models, Animal
  • Fibroblasts
  • Humans
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / pathology*
  • Huntington Disease / therapy
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitophagy*
  • Mutant Proteins / metabolism*
  • Neurons / pathology
  • Peptides / pharmacology
  • Primary Cell Culture
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Proteomics
  • Rats
  • Valosin Containing Protein / antagonists & inhibitors
  • Valosin Containing Protein / metabolism*

Substances

  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Mutant Proteins
  • Peptides
  • VCP protein, human
  • Valosin Containing Protein
  • Vcp protein, mouse