Parkinson’s disease is characterized by abundant α-Synuclein (α-Syn) neuronal inclusions known as Lewy-bodies and Lewy-neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here we found that in wildtype non-transgenic mice a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson’s-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson’s disease.

Synthetic a-Synuclein fibrils injected into the brain spread far beyond the injection site and are sufficient to accelerate Parkinson’s disease–like pathology in mice.

Summary The accumulation and propagation of misfolded α-Synuclein (α-Syn) is a central feature of Parkinson’s disease (PD) 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) α-Syn is bidirectionally restricted. Although fibrils formed by Hu-Ms-α-Syn chimeric mutants can overcome this inhibition in cell-free systems, sequence homology poorly predicts their efficiency in inducing α-Syn pathology in primary neurons or after intracerebral injection into wildtype mice. Chimeric α-Syn fibrils demonstrate enhanced or reduced pathogenicities compared to wildtype Hu- or Ms-α-Syn fibrils. Furthermore, α-Syn mutants induced to polymerize by fibrillar seeds inherit the functional properties of their template, suggesting transferable pathogenic and non-pathogenic states likely influence the initial engagement between exogenous α-Syn seeds with endogenous neuronal α-Syn. Thus, transmission of synucleinopathies is regulated by biological processes in addition to molecular compatibility.