Structural evidence that RNA contributes to polymorphism of tau amyloid fibrils

RNA colocalizes with tau deposits in Alzheimer's disease (AD) and other tauopathies, and drives tau aggregation in vitro. However, molecular details of RNA-tau interactions remain unclear, and in particular whether these interactions contribute to neurodegeneration. Previously, we determined a 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 and seeded by pathological tau fibrils extracted from the postmortem brain of an AD patient. This structure reveals an expanded tau C-terminal core with partial resemblance to AD tau fibrils. RNA sequencing identified 18S ribosomal RNA as the primary fibril-bound species, consistent with the well-documented link between pathological tau and ribosomal dysfunction in neurodegenerative diseases. 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 several pathological polymorphic tau fibrils. All three of our recombinant RNA-tau fibrils dissolve upon RNase treatment, demonstrating that RNA is the molecular glue of these complexes. In the presence of different RNAs, tau fibrils adopt distinct folds, suggesting that RNA is a cofactor that shapes tau fibril polymorphism. Overall design: RNA sequencing of RNA bound to full-length 2N4R tau fibrils formed in the presence of unfractionated mouse liver RNA and Alzheimer's disease brain extracted tau fibrils