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

ABSTRACT: The accumulation and propagation of misfolded ?-synuclein (?-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) ?-Syn is bidirectionally restricted. Although fibrils formed by Hu-Ms-?-Syn chimeric mutants can overcome this inhibition in cell-free systems, sequence homology poorly predicts their efficiency in inducing ?-Syn pathology in primary neurons or after intracerebral injection into wild-type mice. Chimeric ?-Syn fibrils demonstrate enhanced or reduced pathogenicities compared with wild-type Hu- or Ms-?-Syn fibrils. Furthermore, ?-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 ?-Syn seeds and endogenous neuronal ?-Syn. Thus, transmission of synucleinopathies is regulated by biological processes in addition to molecular compatibility.

SUBMITTER: Luk KC 

PROVIDER: S-EPMC5087609 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature