alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivoα-突触核蛋白在移植体内多巴胺神经元细胞间转移和播种.pdfVIP

Alpha-Synuclein Cell-to-Cell Transfer and Seeding in Grafted Dopaminergic Neurons In Vivo 1 1,2 ´ 1 ¨ 3 4 Elodie Angot *, Jennifer A. Steiner , Carla M. Lema Tome , Peter Ekstrom , Bengt Mattsson , ¨ 4, Patrik Brundin1,2 Anders Bjorklund 1 Neuronal Survival Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden, 2 Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, United States of America, 3 ImaGene-iT, Lund, Sweden, 4 Neurobiology Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden Abstract 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, a-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 a-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 a-synuclein. We now demonstrate frequent transfer of a- synuclein from a rat brain engineered to overexpress human a-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell