The Homozygote VCP Mouse Model Exhibits Accelerated Human VCP-Associated Disease Pathology

Valosin containing protein (VCP) mutations are the cause of hereditary inclusion body myopathy, Paget’s disease of bone, frontotemporal dementia (IBMPFD). VCP gene mutations have also been linked to 2% of isolated familial amyotrophic lateral sclerosis (ALS). VCP is at the intersection of disrupted ubiquitin proteasome and autophagy pathways, mechanisms responsible for the intracellular protein degradation and abnormal pathology seen in muscle, brain and spinal cord. We have developed the homozygous knock-in VCP mouse (VCP) model carrying the common R155H mutations, which develops many clinical features typical of the VCP-associated human diseases. Homozygote VCP mice typically survive less than 21 days, exhibit weakness and myopathic changes on EMG. MicroCT imaging of the bones reveal non-symmetrical radiolucencies of the proximal tibiae and bone, highly suggestive of PDB. The VCP mice manifest prominent muscle, heart, brain and spinal cord pathology, including striking mitochondrial abnormalities, in addition to disrupted autophagy and ubiquitin pathologies. The VCP homozygous mouse thus represents an accelerated model of VCP disease and can be utilized to elucidate the intricate molecular mechanisms involved in the pathogenesis of VCP-associated neurodegenerative diseases and for the development of novel therapeutic strategies. Citation: Nalbandian A, Llewellyn KJ, Kitazawa M, Yin HZ, Badadani M, et al. (2012) The Homozygote VCP Mouse Model Exhibits Accelerated Human VCP-Associated Disease Pathology. PLoS ONE 7(9): e46308. doi:10.1371/journal.pone.0046308 Editor: Mel B. Feany, Brigham and Women’s Hospital, Harvard Medical School, United States of America Received June 15, 2012; Accepted August 29, 2012; Published September 28, 2012 Copyright: 2012 Nalbandian et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by National Institutes of Health (NIH) grant AR050236 and Muscular Dystrophy Association (MDA) 175682 to VK; and NS36548 to JW; and National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIH/NIAMS) grant AR054695 to MK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: vkimonis@uci.edu " These authors are joint first authors on this work.