UCLA

Multiple neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) have been associated with the pathological aggregation of amyloid protein α-synuclein (αSyn). Similar to tau strains from different tauopathies, strains of αSyn have been demonstrated distinct cell-to-cell spreading. The distinct biological activity from each strain is encoded by the specific conserved conformation. However, we knew little about the atomic structures of αSyn fibril polymorphs. Our works revealed cryo-EM structures of αSyn wild-type fibril polymorphs and αSyn fibril polymorphs with hereditary mutation (E46K and H50Q). We showed two types of kernel that can be found in all αSyn polymorphs, which is validated by the fibrils from MSA patients. We also found αSyn fibril polymorphs are differed by varying 1) folding of protofilament 2) number of protofilament 3) binding interface between protofilaments, thus leads to distinct cellular toxicity, aggregation rate and seeding capacity. Furthermore, we extracted and characterized fibrils from patients with Parkinson’s disease, which formed a different polymorph. The study provides near-atomic insights about αSyn aggregation and enables future development of therapeutics.