The dual role of c-src in cell-to-cell transmission of ?-synuclein

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons located in the substantia nigra pars compacta and the presence of proteinaceous inclusions called Lewy bodies and Lewy neurites in numerous brain regions. Increasing evidence indicates that Lewy pathology progressively involves additional regions of the nervous system as the disease advances, and the prion-like propagation of ?-synuclein (?-syn) pathology promotes PD progression. Accordingly, the modulation of ?-syn transmission may be important for the development of disease-modifying therapies in patients with PD. Here, we demonstrate that ?-syn fibrils induce c-src activation in neurons, which depends on the Fc?RIIb-SHP-1/-2-c-src pathway and enhances signals for the uptake of ?-syn into neurons. Blockade of c-src activation inhibits the uptake of ?-syn and the formation of Lewy body-like inclusions. Furthermore, the blockade of c-src activation also inhibits the release of ?-syn via activation of autophagy. The brain permeable c-src inhibitor, saracatinib efficiently reduces ?-syn propagation into neighboring regions in an in vivo model system. These results suggest a new therapeutic target against progressive PD.