Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone
Open accessAbstract
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.
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Histopathological analyses consistently show TARDBP, ubiquitin and SQSTM1-positive inclusions in VCP-related diseases.
“Histopathological analyses consistently illustrate TARDBP, ubiquitin and SQSTM1-positive inclusions in VCP-related diseases [244–247].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [244]
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“Moreover, muscle from IBMPFD patients carrying VCP mutations [246] and transgenic mice expressing VCP mutants [244,248,249] display accumulations of SQSTM1- and LC3-positive autopha-”
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- Authors
- Custer, S. K., Neumann, M., Lu, H., Wright, A. C., & Taylor, J. P.
- Affiliations
- St. Jude Children's Research Hospital (US)
- University Hospital Zurich (CH)
- University of Pennsylvania (US)
- Corresponding author
- Taylor, J. Paul
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-02-10
- Volume
- 19
- Issue
- 9
- Pages
- 1741-1755
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2099208822
- Cited by
- 204
- References
- 57
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 11 · 2023: 9 · 2022: 12 · 2021: 11 · 2020: 4 · 2019: 13 · 2018: 12 · 2017: 13 · 2016: 14 · 2015: 10 · 2014: 6 · 2013: 12 · 2012: 23
- FWCI
- 13.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- reroDoc Digital Library (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- VCP/p97, AAA+ ATPase, transgenic mouse model, muscle degeneration, TDP-43 pathology, osteopenia, Paget's disease of bone, NF-κB signaling, frontotemporal dementia, muscle weakness, rimmed vacuoles
- MeSH terms
- Valosin Containing Protein, Adenosine Triphosphatases, Animals, Brain, Disease Models, Animal, DNA-Binding Proteins, Immunohistochemistry, Mice, Transgenic, Osteitis Deformans, Blotting, Western, Muscle, Skeletal, Maze Learning, Cell Cycle Proteins, Myositis, Inclusion Body, Mutation, Missense, Saccharomyces cerevisiae Proteins, Microscopy, Electron, Transmission, Mice, Frontotemporal Dementia
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