The neurodegeneration that occurs in Alzheimer’s disease (AD) is closely associated with the accumulation of pathologic tau protein aggregates that form neurofibrillary tangles. The discovery of a rare genetic form of dementia sheds light on a new pathway that leads to protein buildup in the brain that could be targeted for new therapies.

This work is published in Science in a paper titled, “Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.

A team of researchers at the University of Pennsylvania School of Medicine examined tissue samples from a human brain donor with an unknown neurodegenerative disease. In doing so, they linked a novel mutation in the Valosin-containing protein (VCP) gene (p.Asp395Gly) to the phenotype of a buildup of tau proteins in areas that were degenerating, and neurons with vacuoles.

The team named the newly discovered disease Vacuolar Tauopathy (VT). The neurodegenerative disease is now characterized by the accumulation of neuronal vacuoles and tau protein aggregates.

“Within a cell, you have proteins coming together, and you need a process to also be able to pull them apart, because otherwise everything kind of gets gummed up and doesn’t work. VCP is often involved in those cases where it finds proteins in an aggregate and pulls them apart,” Edward Lee, MD, PhD, assistant professor of pathology and laboratory medicine in the Perelman School of Medicine at the University of Pennsylvania. “We think that the mutation impairs the proteins’ normal ability to break aggregates apart.”

The researchers noted that the tau protein they observed building up looked very similar to the tau protein aggregates seen in Alzheimer’s disease. With these similarities, they aimed to uncover how this VCP mutation is causing this new disease—to aid in finding treatments for this disease and others. Rare genetic causes of diseases can very often offer insight into more prevalent ones.

The researchers first examined the proteins themselves, in addition to studying cells and an animal model, and found that the tau protein buildup is, in fact, due to the VCP mutation.

The authors wrote that, “VCP appeared to exhibit tau disaggregase activity in vitro which was impaired by the p.Asp395Gly mutation.”

Through further experimentation with a mouse animal model, they performed intracerebral microinjection of pathologic tau which led to increased tau aggregates in p.Asp395Gly VCP knock-in mice compared to injected wild-type mice.

These findings, the authors noted, suggest that p.Asp395Gly VCP is an autosomal dominant genetic mutation associated with neurofibrillary degeneration in part due to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.

“What we found in this study is a pattern we’ve never seen before, together with a mutation that’s never been described before,” Lee said. “Given that this mutation inhibits VCP activity, that suggests the converse might be true—that if you’re able to boost VCP activity, that could help break up the protein aggregates. And if that’s true, we may be able to break up tau aggregates not only for this extremely rare disease, but for Alzheimer’s disease and other diseases associated with tau protein aggregation.”

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