Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis

Mutations in alpha -synuclein, a protein highly enriched in presynaptic ter minals, have been implicated in the expression of familial forms of Parkins on's disease (PD) whereas native alpha -synuclein is a major component of i ntraneuronal inclusion bodies characteristic of PD and other neurodegenerat ive disorders. Although overexpression of human a-synuclein induces dopamin ergic nerve terminal degeneration, the molecular mechanism by which alpha - synuclein contributes to the degeneration of these pathways remains enigmat ic, We report here that alpha -synuclein complexes with the presynaptic hum an dopamine transporter (hDAT) in both neurons and cotransfected cells thro ugh the direct binding of the non-A beta amyloid component of alpha -synucl ein to the carboxyl-terminal tail of the hDAT, alpha -Synuclein-hDAT comple x formation facilitates the membrane clustering of the DAT, thereby acceler ating cellular dopamine uptake and dopamine-induced cellular apoptosis, Sin ce the selective vulnerability of dopaminergic neurons in PD has been ascri bed in part to oxidative stress as a result of the cellular overaccumulatio n of dopamine or dopamine-like molecules by the presynaptic DAT, these data provide mechanistic insight into the mode by which the activity of these t wo proteins may give rise to this process.