title: A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA.
authors.forename: Angèle
authors.initials: A
authors.lastname: Nalbandian
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Llewellyn
authors.forename: Mallikarjun
authors.initials: M
authors.lastname: Badadani
authors.forename: Hong Z
authors.initials: HZ
authors.lastname: Yin
authors.forename: Christopher
authors.initials: C
authors.lastname: Nguyen
authors.forename: Veeral
authors.initials: V
authors.lastname: Katheria
authors.forename: Giles
authors.initials: G
authors.lastname: Watts
authors.forename: Jogeshwar
authors.initials: J
authors.lastname: Mukherjee
authors.forename: Jouni
authors.initials: J
authors.lastname: Vesa
authors.forename: Vincent
authors.initials: V
authors.lastname: Caiozzo
authors.forename: Tahseen
authors.initials: T
authors.lastname: Mozaffar
authors.forename: John H
authors.initials: JH
authors.lastname: Weiss
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Kimonis
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010001:Osteitis Deformans / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse