RNA Drives Pathogenicity and Diversity of Tau Strains

Tau aggregation causes neurodegenerative tauopathies. Trans-cellular propagation of tau assemblies of unique structure, i.e., strains, may underlie the diversity of these disorders. Alzheimer's disease (AD), the most common tauopathy, is primarily sporadic in origin. Conformational shifts in tau initiate aggregation, but the precise trigger to convert tau from an inert to a seed-competent form in disease states is unknown. RNA triggers tau fibril formation in vitro and has been observed in association with neurofibrillary tangles in human brain. I tested whether RNA exerts sequence-specific effects on tau assembly and strain formation. Three RNA homopolymers, polyA, polyU, and polyC all bound tau, as assessed by biolayer interferometry, but only polyA triggered detectable fibril formation and seeding in tau biosensors. PolyA:tau seeds and fibrils were sensitive to RNase and dependent upon RNA for assembly and seeding. Other ssRNA and ssDNA sequences, but not double stranded forms, induced seeding in tau in a sequence specific manner. Single stranded-ness as well as sequence were important to induction of tau seeding. RNA sequence was more influential than structure, as tested through compensatory mutations of a ssDNA sequence predicted to form pseudoknots. The origin of RNA influenced the ability of tau to adopt structures that would form stable strains. Human RNA potently induced tau seed formation and created tau conformations that preferentially formed stable strains in a HEK293T cell model, whereas other inducers produced strains that sectored. Seeds from cellular strains, P301S mouse brain, and soluble, but not insoluble, AD brain were sensitive to RNase and not DNase. Tau seeds from progressive supranuclear palsy and corticobasal degeneration were sensitive to benzonase, a nuclease that indiscriminately digests DNA and RNA. Thus, RNA specifically induces stable tau strains, and may trigger the formation of dominant pathological assemblies that propagate in AD, and possibly other tauopathies. Collectively, the data presented in this thesis are the first to demonstrate specificity of tau-RNA interactions that influence the emergence of pathology and diversity of tau strains.