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 alpha-synuclein (alpha-syn) pathology promotes PD progression. Accordingly, the modulation of alpha-syn transmission may be important for the development of disease-modifying therapies in patients with PD. Here, we demonstrate that alpha-syn fibrils induce c-src activation in neurons, which depends on the FcgammaRIIb-SHP-1/-2-c-src pathway and enhances signals for the uptake of alpha-syn into neurons. Blockade of c-src activation inhibits the uptake of alpha-syn and the formation of Lewy body-like inclusions. Furthermore, the blockade of c-src activation also inhibits the release of alpha-syn via activation of autophagy. The brain-permeable c-src inhibitor, saracatinib, efficiently reduces alpha-syn propagation into neighboring regions in an in vivo model system. These results suggest a new therapeutic target against progressive PD.
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