Novel Ubiquitin Neuropathology in Frontotemporal Dementia WithValosin-Containing ProteinGene Mutations

Abstract

Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease of bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in the valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene superfamily. The neuropathology associated with sporadic FTD is heterogeneous and includes tauopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). However, there is limited information on the neuropathology in IBMPFD. We performed a detailed, systematic analysis of the neuropathologic changes in 8 patients with VCP mutations. A novel pattern of ubiquitin pathology was identified in IBMPFD that was distinct from sporadic and familial FTLD-U without VCP gene mutations. This was characterized by ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. In contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and there was no biochemical alteration in the VCP protein. VCP is associated with a variety of cellular activities, including regulation of the ubiquitin-proteasome system. Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways.

Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

“…The mutated amino acids include R93C, R95C R95G, R155C, R155H, R155P, G157R, R159H, R159C, R191Q, L198W, A232E, T262A, and N387H (35)(36)(37)(38)(39). Except for Thr-262, all other mutations were not observed at serine, threonine, tyrosine, or lysine.…”

“…Recently, about a dozen missense mutations in the human VCP gene have been identified as causing inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD), an autosomal dominant inherited disease that affects multiple tissues, including muscle, bone, and the cerebral cortex (35)(36)(37)(38)(39). Although it is now known that VCP is critically involved in the pathogenesis of several types of human disorders, including neurodegeneration, the detailed molecular mechanisms mediated by VCP in neurodegenerative disorders remain to be elucidated.…”

The granulin gene family: from cancer to dementia

“…Other mutations in addition to GRN cause FTD, most notably the microtubuleassociated protein tau (MAPT), (55) and, more rarely, chromatinmodifying protein 2B (CHMP2B) (56) and the valosin-containing protein (VCP). (57) MAPT was the first FTD gene to be identified, and maps in remarkably close proximity to GRN on chromosome 17q21.3. (6,7) Presently the Alzheimer Disease and Frontotemporal Dementia Mutation Database (http:// www.molgen.ua.ac.be/FTDMutations/) records 66 distinct GRN mutations.…”

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

“…The most characteristic features are dystrophic neurites and the presence of TDP-43-positive neuronal cytoplasmic (NCI) and intranuclear inclusions (NII) with a typical lentiform shape, mainly in the neocortex and striatum [Mackenzie et al, 2006a;Josephs et al, 2007;Mackenzie, 2007]. However, the NIIs are not completely specific since they were also found in patients without a GRN mutation [Mackenzie et al, 2006a;Forman et al, 2006b;Josephs et al, 2007], some of which have a mutation in the valosin-containing protein gene (VCP) NFAT ( van der Zee et al, 2007a]. Also, the pathologic phenotype of GRN mutation carriers showed a significant level of heterogeneity, including tau pathology of the non-Alzheimer type, a-synuclein pathology, neuritic plaques, or neurofibrillary tangles, all in addition to the typical FTLDU pathology [Behrens et al, 2007;Leverenz et al, 2007;Brouwers et al, 2007;Spina et al, 2007a].…”