A progressive translational mouse model of human valosin-containing protein disease: The VCPR155H/+ mouse

Angèle Nalbandian, Katrina J. Llewellyn, Mallikarjun Badadani, Hong Z. Yin, Christopher Nguyen, Veeral Katheria, Giles Watts, Jogeshwar Mukherjee, Jouni Vesa, Vincent Caiozzo, Tahseen Mozaffar, John H. Weiss, Virginia E. Kimonis

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)260-270
Number of pages11
JournalMuscle and Nerve
Volume47
Issue number2
DOIs
StatePublished - Feb 2013
Externally publishedYes

Keywords

  • Amyotrophic lateral sclerosis
  • Cytoplasmic inclusions
  • Frontotemporal dementia
  • Inclusion body myopathy
  • Molecular genetics
  • Motor neuron degeneration
  • Paget disease of bone
  • Pathology
  • Valosin-containing protein

ASJC Scopus subject areas

  • Physiology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Physiology (medical)

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