Cited by 204Amyotrophic Lateral Sclerosis ResearchGenetic Neurodegenerative DiseasesMuscle Physiology and Disorders

Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone

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Custer, Sara K., Neumann, Manuela, Lu, Hongbo, Wright, Alexander C., Taylor, J. Paul·2010·Human Molecular Genetics

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.

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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].”

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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
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
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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