| First Author | Luk KC | Year | 2016 |
| Journal | Cell Rep | Volume | 16 |
| Issue | 12 | Pages | 3373-3387 |
| PubMed ID | 27653697 | Mgi Jnum | J:239114 |
| Mgi Id | MGI:5824958 | Doi | 10.1016/j.celrep.2016.08.053 |
| Citation | Luk KC, et al. (2016) Molecular and Biological Compatibility with Host Alpha-Synuclein Influences Fibril Pathogenicity. Cell Rep 16(12):3373-87 |
| abstractText | The accumulation and propagation of misfolded alpha-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-Ms-alpha-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. |
