VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease

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VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease

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dc.contributor.author Badadani, Mallikarjun
dc.contributor.author Nalbandian, Angèle
dc.contributor.author Watts, Giles D.
dc.contributor.author Vesa, Jouni
dc.contributor.author Kitazawa, Masashi
dc.contributor.author Su, Hailing
dc.contributor.author Tanaja, Jasmin
dc.contributor.author Dec, Eric
dc.contributor.author Wallace, Douglas C.
dc.contributor.author Mukherjee, Jogeshwar
dc.contributor.author Caiozzo, Vincent
dc.contributor.author Kimonis, Virginia E.
dc.contributor.author Warman, Matthew L.
dc.date.accessioned 2011-11-09T16:30:15Z
dc.date.issued 2010
dc.identifier.citation Badadani, Mallikarjun, Angéle Nalbandian, Giles D. Watts, Jouni Vesa, Masashi Kitazawa, Hailing Su, Jasmin Tanaja, et. al. 2010. VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease. PLoS ONE 5(10): e13183. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:5343172
dc.description.abstract Dominant mutations in the valosin containing protein (VCP) gene cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). We have generated a knock-in mouse model with the common R155H mutation. Mice demonstrate progressive muscle weakness starting approximately at the age of 6 months. Histology of mutant muscle showed progressive vacuolization of myofibrils and centrally located nuclei, and immunostaining shows progressive cytoplasmic accumulation of TDP-43 and ubiquitin-positive inclusion bodies in quadriceps myofibrils and brain. Increased LC3-II staining of muscle sections representing increased number of autophagosomes suggested impaired autophagy. Increased apoptosis was demonstrated by elevated caspase-3 activity and increased TUNEL-positive nuclei. X-ray microtomography (uCT) images show radiolucency of distal femurs and proximal tibiae in knock-in mice and uCT morphometrics shows decreased trabecular pattern and increased cortical wall thickness. Bone histology and bone marrow derived macrophage cultures in these mice revealed increased osteoclastogenesis observed by TRAP staining suggestive of Paget bone disease. The VCP\(^{R155H/+}\) knock-in mice replicate the muscle, bone and brain pathology of inclusion body myopathy, thus representing a useful model for preclinical studies. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi://10.1371/journal.pone.0013183 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950155/pdf/ en_US
dash.license LAA
dc.subject cell biology en_US
dc.subject genetics and genomics en_US
dc.subject molecular biology en_US
dc.subject neurological disorders en_US
dc.subject cognitive neurology and dementia en_US
dc.subject neuromuscular diseases en_US
dc.title VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Warman, Matthew L.
dc.date.available 2011-11-09T16:30:15Z
dash.affiliation.other HMS^Orthopedic Surgery-Children's Hospital en_US
dash.affiliation.other HMS^Genetics en_US

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