TDP‐43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations

Frontotemporal dementia with inclusion body myopathy and Paget's disease of bone (IBMPFD) 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 (TDP‐43) was recently identified as a major disease protein in the ubiquitin‐positive inclusions of sporadic and familial FTLD‐U. To determine if 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 co‐localized with ubiquitin pathology in IBMPFD including both the 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.