1.94 Å structure of synthetic α-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 decade1–3. 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 propagation9,10. While previous investigations have scrutinized fibrils extracted from MSA brains11, their “protein-only” replication was questioned12and their capacity to induce GCIs in animal models was not explored. Conversely, the synthetic fibril strain 1B13,14assembled from recombinant human aSyn self-replicates autonomouslyin vitroand induces GCIs in mice15, 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 pocket16. 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 demonstratein situusing correlative light-electron microscopy. Our findings underscore structural features of aSyn fibrils pivotal for MSA pathogenesis and provide insights for therapeutic development.