Uncovering Unique Tau Profiles That Distinguish PSP From Other Tauopathies

Principal Investigator: Dr. Todd J. Cohen
The University of North Carolina at Chapel Hill

Progressive supranuclear palsy (PSP) is an incurable neurodegenerative disease that requires creative new approaches to target the underlying pathology that kills brain cells. Central to PSP are aggregates that form in the brain composed of abnormal clumps of the tau protein, and given enough time, these eventually lead to impaired neuron function, behavioral abnormalities, and cognitive deficits. Therefore, the overall goal of our proposal is straight-forward; if we can devise therapies to prevent the abnormal clumping of tau proteins, then we could potentially prevent the onset or progression of PSP. To accomplish such a challenging feat, we require a better understanding of the factors that impact tau’s ability to aggregate. Inside our neurons, proteins are controlled through post-translational modifications (or PTMs), which are chemical tags that allow proteins to communicate within their surrounding environment. One modification that we have studied extensively is called acetylation, a tag that is added to a specific amino acid (lysine) present in many proteins including tau. We have shown that acetylation can dramatically alter tau’s function, including causing its abnormal clumping, or aggregation. We also recently observed that tau acetylation is prominent in PSP patient brain tissue, a chemical tag that could potentially set the stage for disease progression. Therefore, we suspect that abnormal tau modifications, including acetylation, can potentially drive the formation of tau aggregates and subsequent clinical symptoms of PSP. This is the first proposal of its kind to explore unique tau modifications (or profiles) in PSP and test the hypothesis that acetylation at specific sites acts as a potential trigger for this devastating disease. The results of our study could foster new approaches to inhibit tau acetylation, either in cognitively normal but at-risk individuals (as a preventative therapy), or those clinically diagnosed with PSP (as a treatment strategy).