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Muscle Nerve. 2013 Feb;47(2):260-70. doi: 10.1002/mus.23522. Epub 2012 Nov 21.

A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse.

Author information

1
Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA.

Abstract

INTRODUCTION:

Mutations in the valosin-containing protein (VCP) gene cause hereditary inclusion body myopathy (IBM) associated with Paget disease of bone (PDB), and frontotemporal dementia (FTD). More recently, these mutations have been linked to 2% of familial amyotrophic lateral sclerosis (ALS) cases. A knock-in mouse model offers the opportunity to study VCP-associated pathogenesis.

METHODS:

The VCP(R155H/+) knock-in mouse model was assessed for muscle strength and immunohistochemical, Western blot, apoptosis, autophagy, and microPET/CT imaging analyses.

RESULTS:

VCP(R155H/+) mice developed significant progressive muscle weakness, and the quadriceps and brain developed progressive cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies, and increased LC3-II staining. MicroCT analyses revealed Paget-like lesions at the ends of long bones. Spinal cord demonstrated neurodegenerative changes, ubiquitin, and TDP-43 pathology of motor neurons.

CONCLUSIONS:

VCP(R155H/+) knock-in mice represent an excellent preclinical model for understanding VCP-associated disease mechanisms and future treatments.

PMID:
23169451
PMCID:
PMC3556223
DOI:
10.1002/mus.23522
[Indexed for MEDLINE]
Free PMC Article

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