1.94 Angstrom structure of synthetic alpha-synuclein fibrils seeding MSA neuropathology

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown etiology, typically affecting individuals aged 50-60 and leading to patient death within a decade 1–3 . Characterized by the presence of oligodendroglial intracellular aggregates (GCIs) primarily composed of fibrillar alpha-synuclein (aSyn) 4–8 , formation of MSA neuropathology presents similarities to prion propagation 9,10 . While previous investigations have scrutinized fibrils extracted from MSA brains 11 , their “protein-only” replication was questioned 12 and their capacity to induce GCIs in animal models was not explored. Conversely, the synthetic fibril strain 1B 13,14 assembled from recombinant human aSyn self-replicates autonomously in vitro and induces GCIs in mice 15 , suggesting relevance to MSA. Here we report the high-resolution structural analysis of the 1B fibrils revealing similarities with human brain extracted MSA aSyn filaments, particularly the lack of a specific Thioflavin T (ThT) binding pocket 16 . In addition, 1B causes sustained intracerebral GCI spread over the years, prompt lethality in transgenic mice, and transmission of inclusion pathology to wild-type animals after crude brain homogenate inoculation. This points to an underlying prion-like seeding process which we demonstrate in situ using correlative light-electron microscopy. Our findings underscore structural features of aSyn fibrils pivotal for MSA pathogenesis and provide insights for therapeutic development.