Abstract
Participation of the small, intrinsically disordered protein α-synuclein (α-syn) in Parkinson disease (PD) pathogenesis has been well documented. Although recent research demonstrates the involvement of α-syn in mitochondrial dysfunction in neurodegeneration and suggests direct interaction of α-syn with mitochondria, the molecular mechanism(s) of α-syn toxicity and its effect on neuronal mitochondria remain vague. Here we report that at nanomolar concentrations, α-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 α-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 α-syn toxicity in yeast depends on VDAC. The functional interactions between VDAC and α-syn, revealed by the present study, point toward the long sought after physiological and pathophysiological roles for monomeric α-syn in PD and in other α-synucleinopathies.
Highlights
The intrinsically disordered protein ␣-synuclein, a hallmark of Parkinson disease, is involved in mitochondrial dysfunction in neurodegeneration and directly interacts with mitochondria
Supporting our in vitro experiments, a yeast model of Parkinson disease (PD) shows that ␣-syn toxicity in yeast depends on voltage-dependent anion channel (VDAC)
Considering that VDAC is a major conduit for respiratory substrates across the mitochondrial outer membrane (MOM), our results suggest that the functional interaction of monomeric ␣-syn with VDAC could be essential for both physiological adaptation of mitochondrial respiration and dysfunction in PD and other ␣-synucleinopathies
Summary
The intrinsically disordered protein ␣-synuclein, a hallmark of Parkinson disease, is involved in mitochondrial dysfunction in neurodegeneration and directly interacts with mitochondria. Recent research demonstrates the involvement of ␣-syn in mitochondrial dysfunction in neurodegeneration and suggests direct interaction of ␣-syn with mitochondria, the molecular mechanism(s) of ␣-syn toxicity and its effect on neuronal mitochondria remain vague. Because VDAC has been shown to be involved in a wide variety of mitochondria-associated pathologies, including neurodegenerative disorders, such as PD, Alzheimer disease, and amyotrophic lateral sclerosis, VDAC is emerging as a promising pharmacological target [25] This multifunctional channel is regarded as a conjunction point for a variety of cell signals mediated by various cytosolic proteins (26 –28). Considering that VDAC is a major conduit for respiratory substrates across the MOM, our results suggest that the functional interaction of monomeric ␣-syn with VDAC could be essential for both physiological adaptation of mitochondrial respiration and dysfunction in PD and other ␣-synucleinopathies
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