Parkin disrupts the α-synuclein/dopamine transporter interaction: Consequences toward dopamine-induced toxicity

Parkinson's disease is characterized by progressive neuronal degeneration of dopaminergic neurons in the substantia nigra. Many factors are thought to contribute to the neuronal cell death that occurs in Parkinson's disease, including α-synuclein-mediated toxicity. Previously, we have reported that α-synuclein directly couples to the carboxyl tail of the dopamine transporter (DAT) and that the α-synuclein/DAT protein complex formation accelerates DAT-mediated cellular dopamine (DA) uptake and DA-induced cellular apoptosis. In the present study, we report that parkin, an E2-dependent E3 protein ubiquitin ligase associated with recessive early onset Parkinson's disease, exerts a protective effect against DA-induced α-synuclein- dependent cell toxicity. Parkin impairs the α-synuclein/DAT coupling by interacting with the carboxyl-terminus of the DAT and blocks the α-synuclein-induced enhancement in both DAT cell surface expression and DAT-mediated DA uptake. Moreover, we have found that parkin protects against DA-induced cell toxicity in dopaminergic SK-N-SH cells. These findings will help identify the role of these proteins in the etiology and/or maintenance of Parkinson's disease.