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Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation

Conrad C Weihl1, Seema Dalal, Alan Pestronk

  • 1Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA. weihlc@neuro.wustl.edu

Human Molecular Genetics
|December 3, 2005
PubMed

Insights

Mutations in p97/VCP (valosin-containing protein) disrupt the ERAD pathway, leading to protein buildup and cellular dysfunction. This dysfunction may cause inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia (IBMPFD).

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Mutations in the AAA+ protein p97/VCP (valosin-containing protein) cause the rare IBMPFD syndrome.
  • p97/VCP is crucial for endoplasmic reticulum-associated degradation (ERAD), a cellular protein quality control pathway.
  • ERAD removes misfolded proteins from the endoplasmic reticulum for proteasomal degradation.

Purpose of the Study:

  • To investigate the impact of IBMPFD-associated p97/VCP mutations on the ERAD pathway.
  • To determine if these mutations affect protein degradation and cellular aggregation.

Main Methods:

  • Studied p97/VCP mutations (R155H) in cultured cells.
  • Assessed ATPase activity and hexameric structure of mutant p97/VCP.
  • Analyzed ubiquitinated protein levels and degradation of mutant DeltaF508-CFTR.
  • Examined cellular aggregates containing p97/VCP and ubiquitinated proteins.

Main Results:

  • IBMPFD-associated p97/VCP mutations, including R155H, did not alter ATPase activity or structure.
  • Mutant p97/VCP expression increased overall ubiquitinated proteins and impaired DeltaF508-CFTR degradation via ERAD.
  • Cells with IBMPFD mutations showed accumulation of p97/VCP, ubiquitin conjugates, and ER-resident proteins in aggregates.
  • Undegraded DeltaF508-CFTR accumulated within these aggregates.

Conclusions:

  • IBMPFD mutations in p97/VCP disrupt the ERAD pathway's function.
  • Impaired ERAD and subsequent protein aggregation may contribute to IBMPFD pathogenesis.
  • p97/VCP's role in protein quality control is critical for cellular health.

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