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A progressive translational mouse model of human valosin‐containing protein disease: The VCP R155H/+ mouse
Author(s) -
Nalbandian Angèle,
Llewellyn Katrina J.,
Badadani Mallikarjun,
Yin Hong Z.,
Nguyen Christopher,
Katheria Veeral,
Watts Giles,
Mukherjee Jogeshwar,
Vesa Jouni,
Caiozzo Vincent,
Mozaffar Tahseen,
Weiss John H.,
Kimonis Virginia E.
Publication year - 2013
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.23522
Subject(s) - amyotrophic lateral sclerosis , ubiquitin , frontotemporal dementia , pathology , medicine , pathogenesis , autophagy , immunohistochemistry , dementia , biology , disease , apoptosis , gene , genetics
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. Muscle Nerve, 2013