Molecular and Biological Compatibility with Host Alpha-Synuclein Influences Fibril Pathogenicity

The accumulation and propagation of misfolded a-synuclein (alpha-Syn) is a central feature of Parkinson's disease and other synucleinopathies. Molecular compatibility between a fibrillar seed and its native protein state is a major determinant of amyloid self-replication. We show that cross-seeded aggregation of human (Hu) and mouse (Ms) alpha-Syn is bidirectionally restricted. Although fibrils formed by Hu-Msa-Syn chimeric mutants can overcome this inhibition in cell-free systems, sequence homology poorly predicts their efficiency in inducing alpha-Syn pathology in primary neurons or after intracerebral injection into wild-type mice. Chimeric alpha-Syn fibrils demonstrate enhanced or reduced pathogenicities compared with wild-type Hu-or Ms-alpha-Syn fibrils. Furthermore, alpha-Syn mutants induced to polymerize by fibrillar seeds inherit the functional properties of their template, suggesting that transferable pathogenic and non-pathogenic states likely influence the initial engagement between exogenous alpha-Syn seeds and endogenous neuronal alpha-Syn. Thus, transmission of synucleinopathies is regulated by biological processes in addition to molecular compatibility.