TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations.
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.
Neumann
Manuela
M
Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany.
Mackenzie
Ian R
IR
Cairns
Nigel J
NJ
Boyer
Philip J
PJ
Markesbery
William R
WR
Smith
Charles D
CD
Taylor
J Paul
JP
Kretzschmar
Hans A
HA
Kimonis
Virginia E
VE
Forman
Mark S
MS
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
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025801:Ubiquitin; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein