Recent evidence of prion-like propagation of alpha-synuclein (alpha-syn) into neighboring neurons set up a paradigm to elucidate the mechanism of progression of Parkinson's disease (PD) and to develop therapeutic strategies. Here, we show that FcgammaRIIB expressed in neurons functions as a receptor for alpha-syn fibrils and mediates cell-to-cell transmission of alpha-syn. SHP-1 and 2 are activated downstream by alpha-syn fibrils through FcgammaRIIB and play an important role in cell-to-cell transmission of alpha-syn. Also, taking advantage of a co-culture system, we show that cell-to-cell transmission of alpha-syn induces intracellular Lewy body-like inclusion body formation and that the FcgammaRIIB/SHP-1/2 signaling pathway is involved in it. Therefore, the FcgammaRIIB-SHP-1/-2 signaling pathway may be a therapeutic target for the progression of PD. The in vitro system is an efficient tool for further high-throughput screening that can be used for developing a therapeutic intervention in PD.
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