14. Function and Structure of VCP Mutations Leading to Inclusion-Body Myopathy Associated with Paget Disease of Bone and Frontotemporal Dementia

  1. Valerie Askanas MD, PhD and
  2. W. King Engel MD
  1. Cezary Wójcik MD, PhD, DSc

Published Online: 19 DEC 2011

DOI: 10.1002/9781444398311.ch14

Muscle Aging, Inclusion-Body Myositis and Myopathies

Muscle Aging, Inclusion-Body Myositis and Myopathies

How to Cite

Wójcik, C. (2012) Function and Structure of VCP Mutations Leading to Inclusion-Body Myopathy Associated with Paget Disease of Bone and Frontotemporal Dementia, in Muscle Aging, Inclusion-Body Myositis and Myopathies (eds V. Askanas and W. K. Engel), Wiley-Blackwell, Oxford, UK. doi: 10.1002/9781444398311.ch14

Editor Information

  1. Departments of Neurology and Pathology, University of Southern California Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA

Author Information

  1. Department of Anatomy and Cell Biology, Indiana University School of Medicine Evansville Center for Medical Education Evansville, IN, USA

Publication History

  1. Published Online: 19 DEC 2011
  2. Published Print: 27 JAN 2012

ISBN Information

Print ISBN: 9781405196468

Online ISBN: 9781444398311

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Keywords:

  • aggresome;
  • autophagy;
  • endoplasmic reticulum-associated degradation;
  • ERAD;
  • IBMPFD;
  • inclusion-body myopathy associated with Paget disease of the bone and frontotemporal dementia;
  • proteasome;
  • TAR DNA-binding protein 43;
  • TDP-43;
  • ubiquitin;
  • valosin-containing protein;
  • VCP

Summary

Valosin-containing protein (VCP/p97) is an essential, ubiquitous, and highly conserved ATPase involved in multiple cellular activities, including ubiquitin- and proteasome-dependent proteolysis, endoplasmic reticulum structure and function, aggresome formation, autophagy, replication, and membrane fusion. Missense VCP mutations have been described to be associated with inclusion-body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD), a rare autosomal dominant multisystem disorder. The triad of symptoms observed in patients with IBMPFD can be explained by the selective derangement of the role played by VCP in different biological pathways. Paget disease of the bone results from increased nuclear factor κB activation in osteoclasts. Inclusion-body myopathy and frontotemporal dementia result from cell degeneration and death secondary to increased formation of aggresomes and their deficient targeting in myofibers and neurons to autophagic vacuoles. The latter probably results from an altered pattern of protein glycosylation and deficient binding of mutant VCP to oligosaccharide moieties. It involves deficient degradation of multiple cellular proteins, including the nuclear TAR DNA-binding protein 43 (TDP-43) regulatory protein.