RNA interactions drive structural and functional diversification of α-Synuclein fibrils

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Abstract RNA has emerged as a modulator of protein aggregation, yet its structural and functional impact on amyloid assemblies remains unclear. Here we show that RNA acts as a cofactor that reshapes the assembly, structure and activity of α-synuclein (aS) fibrils, a central pathological hallmark of Parkinson’s disease. Although monomeric aS displays minimal RNA-binding propensity, aggregation confers RNA-binding capacity and enables RNA sequestration. RNA present during fibril formation induces a distinct, more compact cross-β architecture, alters elongation dynamics and suppresses secondary nucleation, generating polymorphs with reduced seeding efficiency in the absence of RNA but RNA-dependent propagation. Functionally, protein-only aS fibrils exhibit catalytic activity that is inhibited by RNA, consistent with RNA–fibril interactions on the fibril surface. By contrast, fibrils templated in the presence of RNA lack detectable catalytic activity, indicating RNA-dependent conformational remodeling of functional sites. RNA also reduces proteolytic degradation of fibrils, consistent with stabilization against clearance mechanisms. Transcriptomic analysis reveals preferential enrichment of uridine-rich RNAs and transcripts encoded by Parkinson’s disease–associated genes within RNA–fibril complexes. Together, these findings identify RNA as a structural and functional determinant of aS fibril polymorphism and stability, supporting a model in which nucleic acids contribute to amyloid strain diversification and persistence in synucleinopathies.

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