Abstact

RNA colocalizes with tau deposits in Alzheimer's disease (AD) and drives tau aggregation in vitro. Previously, we determined a cryogenic-electron microscopy (cryo-EM) structure of fibrils of full-length tau bound to unfractionated mammalian RNA, revealing a small tau C-terminal core. Here, we present the cryo-EM structure of fibrils of full-length recombinant tau bound to unfractionated mammalian RNA seeded by AD-extracted tau fibrils. This structure reveals an expanded tau C-terminal core resembling AD tau fibrils. RNA sequencing identified 18S ribosomal RNA as the primary fibril-bound species. Next, we determined the cryo-EM structure of fibrils of full-length recombinant tau bound to mammalian 18S ribosomal RNA, revealing a core that consists of the R2 to R4 repeat domains previously seen in pathological tau fibrils. All our recombinant RNA-tau fibrils dissolve upon RNase treatment. Tau fibrils adopt distinct folds in the presence of different RNAs, suggesting RNA is a cofactor capable of shaping tau fibril polymorphism.