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

Topic: Brain proteins, microglia and lab models

Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM), Paget's disease of the bone, and frontotemporal dementia (IBMPFD). Patient muscle has degenerating fibers, rimmed vacuoles (RVs), and sarcoplasmic inclusions containing ubiquitin and TDP-43 (TARDNA-binding protein 43). In this study, we find that IBMPFD muscle also accumulates autophagosome-associated proteins, Map1-LC3 (LC3), and p62/sequestosome, which localize to RVs. To test whether VCP participates in autophagy, we silenced VCP or expressed adenosine triphosphatase-inactive VCP. Under basal conditions, loss of VCP activity results in autophagosome accumulation. After autophagic induction, these autophagosomes fail to mature into autolysosomes and degrade LC3. Similarly, IBMPFD mutant VCP expression in cells and animals leads to the accumulation of nondegradative autophagosomes that coalesce at RVs and fail to degrade aggregated proteins. Interestingly, TDP-43 accumulates in the cytosol upon autophagic inhibition, similar to that seen after IBMPFD mutant expression. These data implicate VCP in autophagy and suggest that impaired autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation.

@article{ju2009-20008565,
  author  = {Ju, J. S. and Fuentealba, R. A. and Miller, S. E. and Jackson, E. and Piwnica-Worms, D. and Baloh, R. H. and Weihl, C. C.},
  title   = {{Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease}},
  journal = {The Journal of cell biology},
  year    = {2009},
  doi     = {10.1083/jcb.200908115},
  pmid    = {20008565},
  url     = {https://doi.org/10.1083/jcb.200908115}
}

Key findings

• Under basal conditions, loss of VCP activity results in autophagosome accumulation.
• These data implicate VCP in autophagy and suggest that impaired autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation.

Why it matters

This study found that loss of VCP activity causes autophagosomes to accumulate and fail to mature into autolysosomes, and that IBMPFD mutant VCP leads to nondegradative autophagosomes and TDP-43 accumulation. It suggests impaired autophagy explains the pathology in IBMPFD muscle, but it reports no treatment or cure.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1083/jcb.200908115
• PubMed: 20008565
• Original source →
• Free full text: The Journal of Cell Biology →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein Nature genetics · 2004-03-21 · usefulness score 58/100 · Lewy body dementia
• Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia Nature genetics · 2005-07-24 · usefulness score 57/100 · Lewy body dementia
• Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease The Journal of cell biology · 2007-11-01 · usefulness score 55/100 · Lewy body dementia
• TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations Journal of neuropathology and experimental neurology · 2007-02-01 · usefulness score 49/100 · Brain tissue and pathology
• TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia Journal of neurology, neurosurgery, and psychiatry · 2008-10-01 · usefulness score 49/100 · Brain tissue and pathology

Later studies that cite this one

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• Exome sequencing reveals VCP mutations as a cause of familial ALS Neuron · 2010-12-01 · usefulness score 61/100 · How common it is
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration Human molecular genetics · 2010-04-15 · usefulness score 56/100 · Lewy body dementia
• Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death The EMBO journal · 2016-04-21 · usefulness score 53/100 · Lewy body dementia
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• TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2015-04-01 · usefulness score 50/100 · Brain tissue and pathology
• TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97 The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010-06-01 · usefulness score 48/100 · Brain tissue and pathology
• Lysosomal Dysfunction at the Centre of Parkinson's Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis Trends in neurosciences · 2019-11-05 · usefulness score 47/100 · Caregiving

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• VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD Autophagy · 2010-02-22 · usefulness score 47/100
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