2014 Annual Report: 10 Years of Leading Research

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Regulation of Tau Oligomerization by Interaction with TIA-­‐1, a Component of Stress Granules

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Published work from multiple groups indicates that tau phosphorylation causes tau to mis-­‐localize to the soma and dendrites, where TIA-­‐1 is present [20][21][22]. Our preliminary   data   indicates   that   the   TIA-­‐1   binds   the phosphorylated tau. Tau promotes formation of TIA-­‐1 based SGs, and in the process, binding of Tau with TIA-­‐1 stimulates tau misfolding. These data lead us to hypothesize that binding of tau protein to RNA binding proteins stimulate their aggregation to form stress granules, which concomitantly consolidates misfolded tau thereby providing the nidus for formation of tau pathology. The link between tau and SGs is particularly important because primary dysfunction of RNA binding proteins is known to cause neurodegenerative diseases, including Amyotrophic lateral sclerosis and frontotemporal dementia. We hypothesize that secondary dysfunction of RNA binding proteins, caused by tau-­‐induced hyperactive stress granule formation, also causes neurodegeneration. This provides a clear mechanism through which tau pathology can elicit neurodegeneration, and if true, suggests that the interaction of tau with RNA binding proteins plays a pivotal role in the pathophysiology of AD.