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Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease

Jeong-Sun Ju1, Rodrigo A Fuentealba, Sara E Miller

  • 1Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.

The Journal of Cell Biology
|December 17, 2009
PubMed

Insights

Valosin-containing protein (VCP) mutations impair autophagy, leading to protein buildup in inclusion body myopathy (IBM). This study shows VCP dysfunction causes autophagosomes to accumulate, contributing to IBM pathology and TDP-43 aggregation.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Genetics

Background:

  • Mutations in valosin-containing protein (VCP) are linked to inclusion body myopathy (IBM), Paget's disease of bone, and frontotemporal dementia (IBMPFD).
  • Patient muscle tissue in IBMPFD exhibits degenerating fibers, rimmed vacuoles (RVs), and inclusions containing ubiquitin and TDP-43.
  • Autophagosome-associated proteins, Map1-LC3 (LC3) and p62/sequestosome, are found to accumulate in IBMPFD muscle and localize to RVs.

Purpose of the Study:

  • To investigate the role of VCP in the autophagy pathway.
  • To determine if impaired VCP function contributes to the pathological features observed in IBMPFD.

Main Methods:

  • Silencing VCP or expressing ATPase-inactive VCP in cellular and animal models.
  • Analyzing autophagosome accumulation and maturation following VCP activity loss or mutation.
  • Examining the localization and degradation of autophagic proteins (LC3, p62) and aggregated proteins (TDP-43).

Main Results:

  • Loss of VCP activity leads to the accumulation of autophagosomes under basal conditions.
  • Autophagosomes fail to mature into autolysosomes and degrade LC3 in cells with reduced VCP activity or IBMPFD mutant VCP.
  • IBMPFD mutant VCP expression causes nondegradative autophagosome accumulation at RVs and impaired degradation of aggregated proteins, including TDP-43.

Conclusions:

  • VCP plays a critical role in the autophagy process, specifically in autophagosome maturation and cargo degradation.
  • Impaired autophagy due to VCP dysfunction is a key mechanism underlying the muscle pathology in IBMPFD.
  • The accumulation of TDP-43 in IBMPFD may result from impaired autophagic clearance of aggregated proteins.

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