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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 fro... Full description

Journal Title: Journal of neuropathology and experimental neurology 2007-02, Vol.66 (2), p.152-157
Main Author: Neumann, Manuela
Other Authors: Mackenzie, Ian R , Cairns, Nigel J , Boyer, Philip J , Markesbery, William R , Smith, Charles D , Taylor, J Paul , Kretzschmar, Hans A , Kimonis, Virginia E , Forman, Mark S
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: Hagerstown, MD: American Association of Neuropathologists, Inc
ID: ISSN: 0022-3069
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recordid: cdi_proquest_miscellaneous_68979566
title: TDP-43 in the Ubiquitin Pathology of Frontotemporal Dementia With VCP Gene Mutations
format: Article
creator:
  • Neumann, Manuela
  • Mackenzie, Ian R
  • Cairns, Nigel J
  • Boyer, Philip J
  • Markesbery, William R
  • Smith, Charles D
  • Taylor, J Paul
  • Kretzschmar, Hans A
  • Kimonis, Virginia E
  • Forman, Mark S
subjects:
  • Adenosine Triphosphatases - genetics
  • Aged
  • Biological and medical sciences
  • Cell Cycle Proteins - genetics
  • Cerebral Cortex - metabolism
  • Cerebral Cortex - pathology
  • Dementia - genetics
  • Dementia - metabolism
  • Dementia - pathology
  • Diseases of striated muscles. Neuromuscular diseases
  • DNA-Binding Proteins - metabolism
  • Female
  • Human viral diseases
  • Humans
  • Inclusion Bodies - genetics
  • Inclusion Bodies - metabolism
  • Inclusion Bodies - pathology
  • Infectious diseases
  • Male
  • Medical sciences
  • Middle Aged
  • Mutation - genetics
  • Myositis, Inclusion Body - genetics
  • Myositis, Inclusion Body - metabolism
  • Myositis, Inclusion Body - pathology
  • Neurology
  • Neurons - metabolism
  • Neurons - pathology
  • Osteitis Deformans - genetics
  • Osteitis Deformans - metabolism
  • Osteitis Deformans - pathology
  • Ubiquitin - metabolism
  • Valosin Containing Protein
  • Viral diseases
  • Viral diseases of the nervous system
ispartof: Journal of neuropathology and experimental neurology, 2007-02, Vol.66 (2), p.152-157
description: 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0022-3069
fulltext: fulltext
issn:
  • 0022-3069
  • 1554-6578
url: Link


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titleTDP-43 in the Ubiquitin Pathology of Frontotemporal Dementia With VCP Gene Mutations
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creatorcontribNeumann, Manuela ; Mackenzie, Ian R ; Cairns, Nigel J ; Boyer, Philip J ; Markesbery, William R ; Smith, Charles D ; Taylor, J Paul ; Kretzschmar, Hans A ; Kimonis, Virginia E ; Forman, Mark S
descriptionFrontotemporal 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.
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subjectAdenosine Triphosphatases - genetics ; Aged ; Biological and medical sciences ; Cell Cycle Proteins - genetics ; Cerebral Cortex - metabolism ; Cerebral Cortex - pathology ; Dementia - genetics ; Dementia - metabolism ; Dementia - pathology ; Diseases of striated muscles. Neuromuscular diseases ; DNA-Binding Proteins - metabolism ; Female ; Human viral diseases ; Humans ; Inclusion Bodies - genetics ; Inclusion Bodies - metabolism ; Inclusion Bodies - pathology ; Infectious diseases ; Male ; Medical sciences ; Middle Aged ; Mutation - genetics ; Myositis, Inclusion Body - genetics ; Myositis, Inclusion Body - metabolism ; Myositis, Inclusion Body - pathology ; Neurology ; Neurons - metabolism ; Neurons - pathology ; Osteitis Deformans - genetics ; Osteitis Deformans - metabolism ; Osteitis Deformans - pathology ; Ubiquitin - metabolism ; Valosin Containing Protein ; Viral diseases ; Viral diseases of the nervous system
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8Kimonis, Virginia E
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descriptionFrontotemporal 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.
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4Cerebral Cortex - metabolism
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6Dementia - genetics
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9Diseases of striated muscles. Neuromuscular diseases
10DNA-Binding Proteins - metabolism
11Female
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14Inclusion Bodies - genetics
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22Myositis, Inclusion Body - genetics
23Myositis, Inclusion Body - metabolism
24Myositis, Inclusion Body - pathology
25Neurology
26Neurons - metabolism
27Neurons - pathology
28Osteitis Deformans - genetics
29Osteitis Deformans - metabolism
30Osteitis Deformans - pathology
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authorNeumann, Manuela ; Mackenzie, Ian R ; Cairns, Nigel J ; Boyer, Philip J ; Markesbery, William R ; Smith, Charles D ; Taylor, J Paul ; Kretzschmar, Hans A ; Kimonis, Virginia E ; Forman, Mark S
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jtitleJournal of neuropathology and experimental neurology
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abstractFrontotemporal 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.
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pubAmerican Association of Neuropathologists, Inc
pmid17279000
doi10.1097/nen.0b013e31803020b9
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