Molecular mechanism of olesoxime-mediated neuroprotection through targeting α-synuclein interaction with mitochondrial VDAC

• Published in: Cellular and molecular life sciences : CMLS 2020-09, Vol.77 (18), p.3611-3626
• Main Authors: Rovini, Amandine, Gurnev, Philip A., Beilina, Alexandra, Queralt-Martín, María, Rosencrans, William, Cookson, Mark R., Bezrukov, Sergey M., Rostovtseva, Tatiana K.
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Apoptosis; Biochemistry; Bioenergetics; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell differentiation; Cell Line, Tumor; Cell Survival - drug effects; Channel gating; Cholestenones - pharmacology; Cholesterol; Dopamine receptors; Electric potential; Experiments; Gene expression; Humans; Ion channels; Life Sciences; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Lipids; Membrane Potential, Mitochondrial - drug effects; Membranes; Metabolites; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Movement disorders; Neurodegenerative diseases; Neuroprotection; Original Article; Parkinson's disease; Protective Agents - pharmacology; Protein Binding; Protein Transport - drug effects; Proteins; Reactive Oxygen Species - metabolism; Respiration; RNA Interference; RNA, Small Interfering - metabolism; Synuclein; Translocation; Voltage; Voltage-Dependent Anion Channel 1 - antagonists & inhibitors; Voltage-Dependent Anion Channel 1 - genetics; Voltage-Dependent Anion Channel 1 - metabolism
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-019-03386-w

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.