RNA induces unique tau strains and stabilizes Alzheimer disease seeds

Abstract

Tau aggregation causes neurodegenerative tauopathies, and trans-cellular propagation of tau assemblies of unique structure, i.e. strains, may underlie the diversity of these disorders. Polyanions have been reported to induce tau aggregation in vitro, 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. We tested whether RNA exerts sequence-specific effects on tau assembly and strain formation. Three RNA homopolymers, polyA, polyU, and polyC all bound tau, but only polyA triggered seed and fibril formation. PolyA:tau seeds and fibrils were sensitive to RNase. The origin of RNA influenced the ability of tau to adopt a structure 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. Finally, we found that soluble, but not insoluble, seeds from Alzheimers disease (AD) brain were sensitive to RNase. Thus, RNA specifically induces stable tau strains, and may trigger the formation of dominant pathological assemblies that propagate in AD, and possibly other tauopathies.