Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations
Authors
Forman, Mark S.Mackenzie, Ian R.
Cairns, Nigel J.
Swanson, Eric
Boyer, Philip J.
Drachman, David A.
Jhaveri, Bharati S.
Karlawish, Jason H.
Pestronk, Alan
Smith, Thomas W.
Tu, Pang-Hsien
Watts, Giles D. J.
Markesbery, William R.
Smith, Charles D.
Kimonis, Virginia E.
Document Type
Journal ArticlePublication Date
2006-06-20Keywords
Adenosine TriphosphatasesBlotting, Western
Cell Cycle Proteins
Dementia
Female
Humans
Immunohistochemistry
Male
Mutation
Myositis, Inclusion Body
Osteitis Deformans
Ubiquitin
Neurology
Neuroscience and Neurobiology
Metadata
Show full item recordAbstract
Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease of bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in the valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene superfamily. The neuropathology associated with sporadic FTD is heterogeneous and includes tauopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). However, there is limited information on the neuropathology in IBMPFD. We performed a detailed, systematic analysis of the neuropathologic changes in 8 patients with VCP mutations. A novel pattern of ubiquitin pathology was identified in IBMPFD that was distinct from sporadic and familial FTLD-U without VCP gene mutations. This was characterized by ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. In contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and there was no biochemical alteration in the VCP protein. VCP is associated with a variety of cellular activities, including regulation of the ubiquitin-proteasome system. Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways.Source
Forman MS, Mackenzie IR, Cairns NJ, Swanson E, Boyer PJ, Drachman DA, Jhaveri BS, Karlawish JH, Pestronk A, Smith TW, Tu PH, Watts GD, Markesbery WR, Smith CD, Kimonis VE. Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol. 2006 Jun;65(6):571-81. doi: 10.1097/00005072-200606000-00005. PMID: 16783167.
DOI
10.1097/00005072-200606000-00005Permanent Link to this Item
http://hdl.handle.net/20.500.14038/37680PubMed ID
16783167Related Resources
ae974a485f413a2113503eed53cd6c53
10.1097/00005072-200606000-00005