Alpha-Synuclein Cell-to-Cell Transfer and Seeding in Grafted Dopaminergic Neurons In Vivo

Several people with Parkinson's disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10-22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, alpha-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of alpha-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred alpha-synuclein. We now demonstrate frequent transfer of alpha-synuclein from a rat brain engineered to overexpress human alpha-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of alpha-synuclein. Thus, we present evidence both for the involvement of endocytosis in alpha-synuclein uptake in vivo, and for seeding of aggregation of endogenous alpha-synuclein in the recipient neuron by the transferred alpha-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted alpha-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of alpha-synuclein and therefore might retard progression of Parkinson neuropathology.