A team of researchers at the Case Western Reserve University School of Medicine has taken a major step towards understanding the mechanisms involved in the formation of tau protein clumps. Tau protein is a key hallmark of Alzheimer’s disease and several other neurodegenerative disorders.
The tau protein is a major neuronal protein. It plays a key role in Alzheimer’s disease (AD) and several other neurodegenerative disorders. These are collectively classified as tauopathies. These include Pick’s disease, frontotemporal dementia, progressive supranuclear palsy and chronic traumatic encephalopathy. Under normal physiological conditions, tau is localised to axons, where it is involved in the assembly of microtubules. However, in tauopathies, the protein self-associates into different forms of filaments that contain largely hyperphosphorylated tau and have properties of amyloid fibrils. Evidence suggests that tau misfolding and aggregation is one of the key events in disease pathogenesis.
A number of recent reports have indicated that, like some other proteins, purified full-length tau has a high propensity to undergo liquid-liquid phase separation (LLPS). This process results in the formation of liquid-like droplets containing highly concentrated protein. Researchers believe this phenomenon is important for normal cell function. However, under certain conditions, this separation within cells may also have pathological consequences.
Building on these recent reports, researchers in a study, published in PNAS, explored the relationship between pathogenic mutations of tau, protein LLPS and aggregation into amyloid fibrils.
In contrast to previous suggestions, the team found that pathogenic mutations within the pseudorepeat region did not affect tau’s propensity to form liquid droplets. However, they found that LLPS greatly accelerated formation of fibrillar aggregates. In fact, this effect was particularly dramatic for tau variants with disease-related mutations.
The authors also described the mechanism by which LLPS regulates clumping when different variants of tau protein are present. They showed that because of the unique properties of liquid droplets, the presence of a shorter, slowly aggregating tau variant inhibited clumping of a longer, normally fast aggregating variant. This slowed down the overall process of tangle formation.
This novel regulatory mechanism may play a key role in determining the clinical outcome of disease. This is because the ratio of tau isoforms in the brain varies substantially in different tauopathies. For example, AD is characterised by an equal proportion of both isoforms. Whereas fibrillary tangles in progressive supranuclear palsy and Pick’s disease consist largely of the longer and shorter variants, respectively.
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