TDP-43 in the Ubiquitin Pathology of Frontotemporal Dementia With VCP Gene Mutations

• DOI: 10.1097/nen.0b013e31803020b9
• Publication Date: 2008-05-04T14:07:21Z
• Authors: Manuela Neumann; Ian R. Mackenzie; Nigel J. Cairns; Philip J. Boyer; William R. Markes...; Charles D. Smith; J. Paul Taylor; Hans A. Kretzschmar; Virginia E. Kimonis; Mark S. Forman
• Keywords: Male; Aging; TDP-43; Clinical Sciences; Cell Cycle Proteins; Neurodegenerative; frontotemporal dementia; Inclusion Body; Myositis, Inclusion Body; 03 medical and health sciences; Rare Diseases; 0302 clinical medicine; Valosin Containing Protein; ubiquitin; Genetics; Acquired Cognitive Impairment; 2.1 Biological and endogenous factors; Humans; Aetiology; Aged; Adenosine Triphosphatases; Cerebral Cortex; Inclusion Bodies; Neurons; Neurology & Neurosurgery; Myositis; valosin-containing protein; Ubiquitin; Neurosciences; neurodegeneration; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Middle Aged; Osteitis Deformans; Brain Disorders; 3. Good health; DNA-Binding Proteins; Frontotemporal Dementia (FTD); Neurological; Mutation; Dementia; Female

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.