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Updated: Jun 16, 2026
In Vivo Electrophysiological Measurement of Compound Muscle Action Potential from the Forelimbs in Mouse Models of Motor Neuron Degeneration
Published on: June 15, 2018
Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in
Sara K Custer1, Manuela Neumann, Hongbo Lu
1Department of Developmental Neurobiology, St. Jude Children's Research, Hospital, Memphis, TN 38105, USA.
Abstract:
Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a dominantly inherited degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. VCP (p97 in mouse, TER94 in Drosophila melanogaster and CDC48 in Saccharomyces cerevisiae) is a highly conserved AAA(+)-ATPase that regulates a wide array of cellular processes. The mechanism of IBMPFD pathogenesis is unknown. Towards elucidating the pathogenic mechanism we have developed and characterized transgenic mice with ubiquitous expression of wild-type and disease-causing versions of human VCP/p97. Here, we report that mice expressing VCP/p97 harboring the mutations R155H or A232E develop pathology that is limited to muscle, brain and bone, recapitulating the spectrum of disease in humans with IBMPFD. The mice exhibit progressive muscle weakness and pathological examination of muscle shows classic characteristics of inclusion body myopathy including rimmed vacuoles and TDP-43 pathology. The mice exhibit abnormalities in behavioral testing and pathological examination of the brain shows widespread TDP-43 pathology. Furthermore, radiological examination of the skeleton reveals that mutant mice develop severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicate that mutant VCP causes inappropriate activation of the NF-kappaB signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone and brain.
Insights
Transgenic mice expressing mutant valosin-containing protein (VCP) develop inclusion body myopathy, frontotemporal dementia, and Paget's disease of bone, mirroring human IBMPFD. This study reveals VCP mutations activate NF-kappaB signaling, contributing to multi-tissue pathology.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Cell Biology
Background:
- Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a rare, dominantly inherited disorder.
- Mutations in the valosin-containing protein (VCP) gene are the known cause of IBMPFD.
- The precise pathogenic mechanisms underlying IBMPFD remain largely unknown.
Purpose of the Study:
- To elucidate the pathogenic mechanisms of IBMPFD.
- To develop and characterize transgenic mouse models expressing wild-type and mutant human VCP/p97.
- To investigate the cellular and molecular consequences of disease-causing VCP mutations.
Main Methods:
- Generation of transgenic mice expressing wild-type and mutant (R155H, A232E) human VCP/p97.
- Phenotypic characterization of mutant mice, including muscle, brain, and bone pathology assessment.
- Behavioral testing and in vitro studies of NF-kappaB signaling activation.
Main Results:
- Mutant VCP/p97 transgenic mice recapitulated the full spectrum of IBMPFD pathology in muscle, brain, and bone.
- Mice exhibited progressive muscle weakness, rimmed vacuoles, and TDP-43 pathology in muscles and brains.
- Skeletal abnormalities included severe osteopenia and focal lesions, alongside inappropriate NF-kappaB signaling activation in vitro.
Conclusions:
- Transgenic mice expressing mutant VCP serve as a relevant model for studying IBMPFD pathogenesis.
- VCP mutations contribute to IBMPFD by causing multi-tissue pathology, potentially through NF-kappaB pathway dysregulation.
- Further research into VCP function and NF-kappaB signaling is crucial for developing therapeutic strategies for IBMPFD.
