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

Authors
  • Rovini, Amandine1, 2
  • Gurnev, Philip A.1
  • Beilina, Alexandra3
  • Queralt-Martín, María1
  • Rosencrans, William1, 4
  • Cookson, Mark R.3
  • Bezrukov, Sergey M.1
  • Rostovtseva, Tatiana K.1
  • 1 Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Bldg. 29B, Room 1G09, Bethesda, MD, 20892-0924, USA , Bethesda (United States)
  • 2 Medical University of South Carolina, Charleston, SC, 29425, USA , Charleston (United States)
  • 3 National Institutes of Health, Bethesda, MD, 20892, USA , Bethesda (United States)
  • 4 Colgate University, Hamilton, NY, 13346, USA , Hamilton (United States)
Type
Published Article
Journal
Cellular and Molecular Life Sciences
Publisher
Springer-Verlag
Publication Date
Nov 23, 2019
Volume
77
Issue
18
Pages
3611–3626
Identifiers
DOI: 10.1007/s00018-019-03386-w
Source
Springer Nature
Keywords
License
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Abstract

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.

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