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

• Published in: Human molecular genetics Vol. 19; no. 9; pp. 1741 - 1755
• Main Authors: Custer, Sara K., Neumann, Manuela, Lu, Hongbo, Wright, Alexander C., Taylor, J. Paul
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2010
• Subjects: Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Animals; Biological and medical sciences; Blotting, Western; Brain - pathology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Disease Models, Animal; DNA-Binding Proteins - metabolism; Drosophila melanogaster; Frontotemporal Dementia - complications; Frontotemporal Dementia - genetics; Frontotemporal Dementia - pathology; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Immunohistochemistry; Maze Learning; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Molecular and cellular biology; Muscle, Skeletal - ultrastructure; Mutation, Missense - genetics; Myositis, Inclusion Body - complications; Myositis, Inclusion Body - genetics; Myositis, Inclusion Body - pathology; Osteitis Deformans - complications; Osteitis Deformans - genetics; Osteitis Deformans - pathology; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Valosin Containing Protein; Osteoarticular system; Central nervous system; Transgenic animal; Genetics; Degeneration; Muscle; Mutation; Bone; Encephalon; Spectrum
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddq050

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-κB signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone and brain.