Alzheimer’s disease (AD) is a fatal neurodegenerative disease in which progressive brain degeneration compromises cognitive function. AD neurodegeneration is tightly associated with abnormal neuronal inclusions called neurofibrillary tangles, which are composed of aggregated tau protein. The importance of tau protein in dementia is highlighted by various known autosomal-dominant mutations in MAPT (microtubule-associated protein tau), the gene that encodes for tau, that are associated with frontotemporal lobar degeneration with tau inclusions (FTLD-tau). Identifying additional disease-causing genes that affect tau accumulation, including genes involved in protein quality control and tau clearance, has the potential to reveal previously unknown mechanisms that maintain neuronal health.

Two families were identified with autosomal-dominant dementia linked to a p.Asp395Gly mutation in VCP. Valosin-containing protein (VCP) is a AAA+ [adenosine triphosphatases (ATPases) associated with diverse cellular activities] protein and uses energy from adenosine 5′-triphosphate (ATP) hydrolysis to unfold substrates to assist the dismantling of macromolecular complexes. Other VCP mutations have been identified in a disease called multisystem proteinopathy (MSP), which is associated with neuronal TDP-43 [TAR DNA-binding protein 43] protein inclusions. The mechanisms by which p.Asp395Gly VCP leads to neurodegeneration are unknown.

Two kindred were identified with an autosomal-dominant inheritance pattern of frontotemporal degeneration linked to a p.Asp395Gly VCP mutation. We have named this disease vacuolar tauopathy because of the presence of neuronal vacuoles and tau aggregates. Tau aggregates were morphologically and biochemically similar to AD neurofibrillary tangles. Moreover, the presence of vacuoles and neurofibrillary tangles in the brain were inversely correlated. Degenerating brain regions such as the frontal neocortex exhibited tau aggregation, whereas nondegenerating brain regions such as the visual cortex exhibited vacuolization. To further characterize the p.Asp395Gly VCP mutation, we assessed recombinant VCP proteins for ATPase activity in an in vitro assay. This approach demonstrated that p.Asp395Gly VCP exhibited a partial loss of ATPase activity, in contrast with MSP mutations, which increase ATPase activity. Given that VCP unfolds protein substrates, we hypothesized that VCP may disaggregate pathologic tau aggregates. Indeed, VCP appeared to partially disaggregate pathologic tau aggregates derived from AD human brain tissues, and the p.Asp395Gly mutation impaired this activity. VCP activity against pathologic tau was energy (ATP) dependent and required polyubiquitination of the tau substrate. In addition, expression of p.Asp395Gly VCP in a cell culture model of tau aggregation was associated with enhanced accumulation of cellular tau aggregates. Last, we generated mice in which the p.Asp395Gly mutation was knocked in, which exhibited a minimal phenotype when unchallenged. However, upon initiating tau aggregation through microinjection of pathologic AD tau extracts into the mouse brain, mutant VCP mice showed an increase in tau accumulation compared with that of wild-type animals.

We describe a partial loss-of-function mutation in VCP that was associated with a neurodegenerative disease, which we named vacuolar tauopathy. VCP appeared to exhibit activity that promoted the disruption of tau aggregates in an energy- and polyubiquitin-dependent manner. Furthermore, the p.Asp395Gly VCP mutation enhanced …