title: TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations.
abstract: Frontotemporal dementia with inclusion body myopathy and Paget disease of bone is a rare, autosomal-dominant 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.
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Boyer
authors.forename: William R
authors.initials: WR
authors.lastname: Markesbery
authors.forename: Charles D
authors.initials: CD
authors.lastname: Smith
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Kimonis
authors.forename: Mark S
authors.initials: MS
authors.lastname: Forman
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics*; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003704:Dementia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D018979:Myositis, Inclusion Body / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010001:Osteitis Deformans / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025801:Ubiquitin; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein