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.

Cytoplasmic inclusions containing ␣-synuclein (␣-Syn) fibrils, referred to as Lewy bodies (LBs), are the signature neuropathological hallmarks of Parkinson's disease (PD). Although ␣-Syn fibrils can be generated from recombinant ␣-Syn protein in vitro, the production of fibrillar ␣-Syn inclusions similar to authentic LBs in cultured cells has not been achieved. We show here that intracellular ␣-Syn aggregation can be triggered by the introduction of exogenously produced recombinant ␣-Syn fibrils into cultured cells engineered to overexpress ␣-Syn. Unlike unassembled ␣-Syn, these ␣-Syn fibrils ''seeded'' recruitment of endogenous soluble ␣-Syn protein and their conversion into insoluble, hyperphosphorylated, and ubiquitinated pathological species. Thus, this cell model recapitulates key features of LBs in human PD brains. Also, these findings support the concept that intracellular ␣-Syn aggregation is normally limited by the number of active nucleation sites present in the cytoplasm and that small quantities of ␣-Syn fibrils can alter this balance by acting as seeds for aggregation.Parkinson's disease ͉ pathology ͉ protein misfolding