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Updated: May 18, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
The homozygote VCP(R¹⁵⁵H/R¹⁵⁵H) mouse model exhibits accelerated human VCP-associated disease pathology
Angèle Nalbandian1, Katrina J Llewellyn, Masashi Kitazawa
1Department of Pediatrics, University of California Irvine, Irvine, California, United States of America.
Abstract:
Valosin containing protein (VCP) mutations are the cause of hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia (IBMPFD). VCP gene mutations have also been linked to 2% of isolated familial amyotrophic lateral sclerosis (ALS). VCP is at the intersection of disrupted ubiquitin proteasome and autophagy pathways, mechanisms responsible for the intracellular protein degradation and abnormal pathology seen in muscle, brain and spinal cord. We have developed the homozygous knock-in VCP mouse (VCP(R155H/R155H)) model carrying the common R155H mutations, which develops many clinical features typical of the VCP-associated human diseases. Homozygote VCP(R155H/R155H) mice typically survive less than 21 days, exhibit weakness and myopathic changes on EMG. MicroCT imaging of the bones reveal non-symmetrical radiolucencies of the proximal tibiae and bone, highly suggestive of PDB. The VCP(R155H/R155H) mice manifest prominent muscle, heart, brain and spinal cord pathology, including striking mitochondrial abnormalities, in addition to disrupted autophagy and ubiquitin pathologies. The VCP(R155H/R155H) homozygous mouse thus represents an accelerated model of VCP disease and can be utilized to elucidate the intricate molecular mechanisms involved in the pathogenesis of VCP-associated neurodegenerative diseases and for the development of novel therapeutic strategies.
Insights
Valosin-containing protein (VCP) mutations cause rare neurodegenerative diseases. A new VCP(R155H/R155H) mouse model exhibits key disease features, offering insights into pathogenesis and therapeutic strategies.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Pathology
Background:
- Valosin-containing protein (VCP) mutations cause hereditary inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia (IBMPFD).
- VCP gene mutations are also implicated in familial amyotrophic lateral sclerosis (ALS).
- VCP is crucial for protein degradation pathways (ubiquitin-proteasome and autophagy), and its dysfunction leads to cellular pathology.
Purpose of the Study:
- To develop and characterize a novel mouse model for VCP-associated diseases.
- To investigate the clinical and pathological features of the VCP(R155H/R155H) mouse model.
- To utilize this model for understanding disease mechanisms and developing therapeutic strategies.
Main Methods:
- Development of a homozygous knock-in VCP mouse model (VCP(R155H/R155H)) with a common R155H mutation.
- Clinical assessment including survival, weakness, and electromyography (EMG).
- MicroCT imaging for bone pathology and histopathological analysis of muscle, heart, brain, and spinal cord.
Main Results:
- The VCP(R155H/R155H) mice exhibit a shortened lifespan (<21 days) with pronounced weakness and myopathic changes.
- MicroCT revealed bone abnormalities suggestive of Paget's disease of bone (PDB).
- Pathological findings include muscle, heart, brain, and spinal cord abnormalities, mitochondrial dysfunction, and disrupted protein degradation pathways.
Conclusions:
- The VCP(R155H/R155H) homozygous mouse is an accelerated model for VCP-associated diseases.
- This model recapitulates key clinical and pathological features of human IBMPFD, PDB, and ALS.
- The model provides a valuable tool for studying VCP disease pathogenesis and testing novel therapeutics.
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