The study by Luk et al. investigates the transmission of pathological α-Synuclein (α-Syn) and its role in Parkinson's disease (PD). In wild-type non-transgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn, resulting in the formation of Lewy bodies and Lewy neurites in interconnected regions. This transmission resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta (SNpc), reduced dopamine levels, and motor deficits. The findings establish a mechanistic link between the transmission of pathologic α-Syn and the key features of PD, including Lewy body formation and dopamine neuron degeneration. The study also highlights the importance of inter-neuronal connectivity in the propagation of α-Syn pathology, suggesting that α-Syn misfolding and fibrillization are upstream events in the progression of PD.The study by Luk et al. investigates the transmission of pathological α-Synuclein (α-Syn) and its role in Parkinson's disease (PD). In wild-type non-transgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn, resulting in the formation of Lewy bodies and Lewy neurites in interconnected regions. This transmission resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta (SNpc), reduced dopamine levels, and motor deficits. The findings establish a mechanistic link between the transmission of pathologic α-Syn and the key features of PD, including Lewy body formation and dopamine neuron degeneration. The study also highlights the importance of inter-neuronal connectivity in the propagation of α-Syn pathology, suggesting that α-Syn misfolding and fibrillization are upstream events in the progression of PD.