α-Synuclein Shows High Affinity Interaction with Voltage-dependent Anion Channel, Suggesting Mechanisms of Mitochondrial Regulation and Toxicity in Parkinson Disease

Participation of the small, intrinsically disordered protein alpha-synuclein (alpha-syn) in Parkinson disease (PD) pathogenesis has been well documented. Although recent research demonstrates the involvement of alpha-syn in mitochondrial dysfunction in neurodegeneration and suggests direct interaction of alpha-syn with mitochondria, the molecular mechanism(s) of alpha-syn toxicity and its effect on neuronal mitochondria remain vague. Here we report that at nanomolar concentrations, alpha-syn reversibly blocks the voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane that controls most of the metabolite fluxes in and out of the mitochondria. Detailed analysis of the blockage kinetics of VDAC reconstituted into planar lipid membranes suggests that alpha-syn is able to translocate through the channel and thus target complexes of the mitochondrial respiratory chain in the inner mitochondrial membrane. Supporting our in vitro experiments, a yeast model of PD shows that alpha-syn toxicity in yeast depends on VDAC. The functional interactions between VDAC and alpha-syn, revealed by the present study, point toward the long sought after physiological and pathophysiological roles for monomeric alpha-syn in PD and in other alpha-synucleinopathies.