VCP Mutations Causing Frontotemporal Lobar Degeneration Disrupt Localization of TDP-43 and Induce Cell Death

摘要: Frontotemporal lobar degeneration (FTLD) with inclusion body myopathy and Paget disease of bone is a rare, autosomal dominant disorder caused by mutations in the VCP (valosin-containing protein) gene. The characterized neuropathologically frontal temporal atrophy, neuron loss gliosis, ubiquitin-positive inclusions (FTLD-U), which are distinct from those seen other sporadic familial FTLD-U entities. major component ubiquitinated FTLD mutation TDP-43 (TAR DNA-binding protein 43 kDa). proteinopathy links amyotrophic lateral sclerosis, FTLD-U, most forms FTLD-U. Understanding relationship between individual gene defects pathologic will facilitate characterization mechanisms leading to neurodegeneration. Using cell culture models, we have investigated role mutant intracellular trafficking, proteasomal function, death demonstrate that 1) alter localization nucleus cytosol, 2) decrease proteasome activity, 3) induce endoplasmic reticulum stress, 4) increase markers apoptosis, 5) impair viability. These results suggest mutation-induced neurodegeneration mediated several mechanisms.