Journal
MUSCLE & NERVE
Volume 47, Issue 2, Pages 260-270Publisher
WILEY
DOI: 10.1002/mus.23522
Keywords
amyotrophic lateral sclerosis; cytoplasmic inclusions; frontotemporal dementia; inclusion body myopathy; molecular genetics; motor neuron degeneration; Paget disease of bone; pathology; valosin-containing protein
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Funding
- National Institutes of Health [AR050236]
- Muscular Dystrophy Association [MDA175682, NS36548]
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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 VCPR155H/+ knock-in mouse model was assessed for muscle strength and immunohistochemical, Western blot, apoptosis, autophagy, and microPET/CT imaging analyses. Results: VCPR155H/+ 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: VCPR155H/+ knock-in mice represent an excellent preclinical model for understanding VCP-associated disease mechanisms and future treatments. Muscle Nerve 47: 260-270, 2013
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