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505171 
Journal Article 
TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations 
Neumann, M; Mackenzie, IR; Cairns, NJ; Boyer, PJ; Markesbery, WR; Smith, CD; Taylor, JP; Kretzschmar, HA; Kimonis, VE; Forman, MS 
2007 
Yes 
Journal of Neuropathology and Experimental Neurology
ISSN: 0022-3069
EISSN: 1554-6578 
66 
2 
152-157 
English 
Frontotemporal dementia with inclusion body myopathy and Paget disease of bone is a rare, autosomal-dorninant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by, a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) without VCP mutations. TAR DNA binding protein 43 (TDP-43) was recently identified as a major disease protein in the ubiquitin-positive inclusions of sporadic and familial FTLD-U. To determine whether the ubiquitin pathology associated with mutations in VCP is characterized by the accumulation of TDP-43, we analyzed TDP-43 in the CNS pathology of five patients with VCP gene mutations. Accumulations of TDP-43 colocalized with ubiquitin pathology in inclusion body myopathy and Paget disease of bone, including both intranuclear inclusions and dystrophic neurites. Similar to FTLD-U, phosphorylated TDP-43 was detected only in insoluble brain extracts from affected brain regions. Identification of TDP-43, but not VCP, within ubiquitin-positive inclusions supports the hypothesis that VCP gene mutations lead to a dominant negative loss or alteration of VCP function culminating in impaired degradation of TDP-43. TDP-43 is a common pathologic substrate linking a variety of distinct patterns of FTLD-U pathology caused by different genetic alterations. 
frontotemporal dementia; neurodegeneration; TDP-43; ubiquitin; valosin-containing protein; amyotrophic-lateral-sclerosis; valosin-containing-protein; inclusion-body myopathy; nuclear factor tdp-43; lobar degeneration; neurodegenerative diseases; endoplasmic-reticulum; paget-disease; progranulin; tau