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Updated: May 16, 2026
Mouse Models of Periventricular Leukomalacia
Published on: May 18, 2010
A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse
Angèle Nalbandian1, Katrina J Llewellyn, Mallikarjun Badadani
1Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA.
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.
Insights
Valosin-containing protein (VCP) gene mutations cause progressive muscle weakness and neurodegeneration. The VCP(R155H/+) knock-in mouse model effectively mimics VCP-associated diseases for therapeutic research.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Mutations in the valosin-containing protein (VCP) gene are linked to hereditary inclusion body myopathy (IBM), Paget disease of bone (PDB), frontotemporal dementia (FTD), and 2% of familial amyotrophic lateral sclerosis (ALS) cases.
- A VCP knock-in mouse model provides a valuable tool for investigating the pathogenesis of VCP-associated disorders.
Purpose of the Study:
- To characterize the VCP(R155H/+) knock-in mouse model for its utility in studying VCP-associated diseases.
- To evaluate the pathological and physiological changes in this mouse model.
Main Methods:
- Assessment of muscle strength, immunohistochemistry, Western blot, apoptosis, autophagy, and microPET/CT imaging in VCP(R155H/+) mice.
- Analysis of spinal cord and long bone pathology.
Main Results:
- VCP(R155H/+) mice exhibited progressive muscle weakness and neurodegenerative changes in the spinal cord.
- Cytoplasmic accumulation of TDP-43 and ubiquitin-positive inclusions were observed in the quadriceps and brain.
- Paget-like bone lesions were identified in the long bones of affected mice.
Conclusions:
- The VCP(R155H/+) knock-in mouse is a robust preclinical model for VCP-associated diseases.
- This model facilitates the study of disease mechanisms and the development of novel therapeutic strategies.
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