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

Elife. 2017 Mar 21;6:e17834. doi: 10.7554/eLife.17834.


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.

Keywords: D. melanogaster; degenerative disease; human; mitochondria; neuroscience; therapeutic treatment.

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Drosophila
  • Drosophila Proteins / metabolism*
  • Enzyme Inhibitors / administration & dosage*
  • Fibroblasts / physiology
  • Frontotemporal Dementia / physiopathology*
  • Humans
  • Membrane Proteins / metabolism*
  • Muscular Dystrophies, Limb-Girdle / physiopathology*
  • Mutant Proteins / antagonists & inhibitors*
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Myositis, Inclusion Body / physiopathology*
  • Osteitis Deformans / physiopathology*
  • Treatment Outcome
  • Valosin Containing Protein / antagonists & inhibitors*
  • Valosin Containing Protein / genetics
  • Valosin Containing Protein / metabolism


  • Drosophila Proteins
  • Enzyme Inhibitors
  • Marf protein, Drosophila
  • Membrane Proteins
  • Mutant Proteins
  • Valosin Containing Protein

Supplementary concepts

  • Inclusion Body Myopathy With Early-Onset Paget Disease And Frontotemporal Dementia