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

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 protei...

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Autores principales: Ju, Jeong-Sun, Fuentealba, Rodrigo A., Miller, Sara E., Jackson, Erin, Piwnica-Worms, David, Baloh, Robert H., Weihl, Conrad C.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806317/
https://www.ncbi.nlm.nih.gov/pubmed/20008565
http://dx.doi.org/10.1083/jcb.200908115
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author Ju, Jeong-Sun
Fuentealba, Rodrigo A.
Miller, Sara E.
Jackson, Erin
Piwnica-Worms, David
Baloh, Robert H.
Weihl, Conrad C.
author_facet Ju, Jeong-Sun
Fuentealba, Rodrigo A.
Miller, Sara E.
Jackson, Erin
Piwnica-Worms, David
Baloh, Robert H.
Weihl, Conrad C.
author_sort Ju, Jeong-Sun
collection PubMed
description 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.
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spelling pubmed-28063172010-06-14 Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease Ju, Jeong-Sun Fuentealba, Rodrigo A. Miller, Sara E. Jackson, Erin Piwnica-Worms, David Baloh, Robert H. Weihl, Conrad C. J Cell Biol Research Articles 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. The Rockefeller University Press 2009-12-14 /pmc/articles/PMC2806317/ /pubmed/20008565 http://dx.doi.org/10.1083/jcb.200908115 Text en © 2009 Ju et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Ju, Jeong-Sun
Fuentealba, Rodrigo A.
Miller, Sara E.
Jackson, Erin
Piwnica-Worms, David
Baloh, Robert H.
Weihl, Conrad C.
Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease
title Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease
title_full Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease
title_fullStr Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease
title_full_unstemmed Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease
title_short Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease
title_sort valosin-containing protein (vcp) is required for autophagy and is disrupted in vcp disease
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806317/
https://www.ncbi.nlm.nih.gov/pubmed/20008565
http://dx.doi.org/10.1083/jcb.200908115
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