Tau aggregates are insoluble, fibrillar accumulations of microtubule associated protein tau (MAPT) that are observed in the brains of patients with more than 20 different neurodegenerative diseases including Alzheimer’s disease (AD) and subtypes of frontotemporal dementia. How these fibrils form in patients and how they alter neuronal function are both unknown. In vitro, RNA promotes the conversion of tau from a soluble form to an insoluble fibrillar aggregate. RNA and RNA binding proteins are also sequestered into tau aggregates in the brains of patients.
I set out to better understand the role that of RNA and RNA binding proteins play in tauopathies and this led to new insights into the composition, origin, and cellular effects of tau aggregates. Specifically, I isolated and sequenced RNA from tau aggregates in two model systems and found enrichment of small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs). As a result, I investigated tau’s interaction with nuclear membraneless organelles that contains a high concentration of snRNAs, known as splicing speckles. I found that tau aggregates localize to splicing speckles and alter their composition, organization, and dynamics. Consistent with these observations, I also found that inducing tau aggregation is sufficient to alter RNA splicing. Unexpectedly, multiple splicing speckle components mislocalized from the nucleus to cytoplasmic tau aggregates. I chose one of these proteins, SRRM2, to investigate further and found it mislocalized to cytoplasmic tau aggregates in three different human tauopathies, including AD. Using CRISPR, I then mapped the domains of SRRM2 and found that poly-serine repeats in its C-terminus are both necessary and sufficient for its interaction with tau aggregates. Further, I also discovered that tau aggregates can merge with and nucleate from the surface of SRRM2 positive cytoplasmic assemblies. I hope that these insights will lead to a better understanding of how tau aggregates form, their role in disease, and lead to therapeutics that can help patients and their families suffering from these devastating neurologic conditions.</p
