Open AccessMolecular mechanism of olesoxime-mediated neuroprotection through targeting α-synuclein interaction with mitochondrial VDAC
Author(s) -
Amandine Rovini,
Philip A. Gurnev,
Alexandra Beilina,
María Queralt-Martín,
William M. Rosencrans,
Mark Cookson,
Sergey M. Bezrukov,
Tatiana K. Rostovtseva
Publication year - 2019
Publication title -
cellular and molecular life sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.928
H-Index - 223
eISSN - 1420-9071
pISSN - 1420-682X
DOI - 10.1007/s00018-019-03386-w
Subject(s) - voltage dependent anion channel , neuroprotection , microbiology and biotechnology , mitochondrion , gating , biology , bioenergetics , bacterial outer membrane , chromosomal translocation , chemistry , biochemistry , biophysics , neuroscience , gene , escherichia coli
An intrinsically disordered neuronal protein α-synuclein (αSyn) is known to cause mitochondrial dysfunction, contributing to loss of dopaminergic neurons in Parkinson's disease. Through yet poorly defined mechanisms, αSyn crosses mitochondrial outer membrane and targets respiratory complexes leading to bioenergetics defects. Here, using neuronally differentiated human cells overexpressing wild-type αSyn, we show that the major metabolite channel of the outer membrane, the voltage-dependent anion channel (VDAC), is a pathway for αSyn translocation into the mitochondria. Importantly, the neuroprotective cholesterol-like synthetic compound olesoxime inhibits this translocation. By applying complementary electrophysiological and biophysical approaches, we provide mechanistic insights into the interplay between αSyn, VDAC, and olesoxime. Our data suggest that olesoxime interacts with VDAC β-barrel at the lipid-protein interface thus hindering αSyn translocation through the VDAC pore and affecting VDAC voltage gating. We propose that targeting αSyn translocation through VDAC could represent a key mechanism for the development of new neuroprotective strategies.