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

Targeting the Multiple Physiologic Roles of VDAC With Steroids and Hydrophobic Drugs

“…The absence of structural data on VDAC closed states makes further speculations unjustified. The gating asymmetry depends on lipid composition: gating is almost symmetrical in the membranes made of dioleoylphosphatidylcholine (DOPC) (Rostovtseva et al, 2006) or of soybean Polar Lipid Extract (PLE) (Cheng et al, 2019;Rovini et al, 2019) (Figures 4A-C), while it is markedly asymmetrical in diphytanoyl-phosphatidylcholine (DPhPC) (Eddy et al, 2012; Figure 3D) or dioleoyl-phosphatidylethanolamine (DOPE) membranes (Rostovtseva et al, 2006). It was demonstrated that the gating asymmetry is enhanced in the presence of nonlamellar lipids, such as DOPE or cardiolipin -they promote channel closure at the negative voltage polarity (Rostovtseva et al, 2006).…”

“…In (A,C,D), VDAC was purified from rat liver mitochondria and recombinant mVDAC1 was used in (B). (A,C) Were adapted by permission from Springer Nature: Springer International Publishing Cellular and Molecular Life Sciences (Rovini et al, 2019) issues which must be taken into account when analyzing a system of channels reconstituted in planar lipid bilayers. Indeed, hydrophobic compounds may have limited partitioning to the lipid membrane, preferring to stay in the detergent mixed micelles in the membrane-bathing buffer solution instead.…”

“…Indeed, for a particular compound, a combination of all three types of interactions is also feasible. Adapted by permission from Springer Nature: Springer International Publishing Cellular and Molecular Life Sciences (Rovini et al, 2019), Copyright (2019).…”

“…An additional characterization using photoaffinity labeling with mass spectrometry identified a cholesterol binding pocket in the lipid-facing outer surface of the mVDAC1 β-barrel coordinated by the membrane-facing residue E73 (Budelier et al, 2017). Cholesterol is, maybe, the clearest example of a hydrophobic (Budelier et al, 2017) MD Simulations (Weiser et al, 2014b) No (Queralt-Martin et al, 2019) No (Queralt-Martin et al, 2019) Yes (van Blitterswijk et al, 1987;Weinrich et al, 2009) Allopregnanolone Photoaffinity labeling (Cheng et al, 2019) No (Cheng et al, 2019) No (Cheng et al, 2019) Yes (Alakoskela et al, 2007;Cheng et al, 2019) Olesoxime Photoaffinity labeling (Bordet et al, 2007) Yes (Rovini et al, 2019) No (Rovini et al, 2019) No (Rovini et al, 2019) Propofol Photoaffinity labeling (Weiser et al, 2013;Weiser et al, 2014a) Yes (Weiser et al, 2014a) No (Weiser et al, 2014a) No (Bahri et al, 2007;Weiser et al, 2014a) Itraconazole Photoaffinity labeling and affinity pulldown (Head et al, 2015) TBD TBD TBD Efsevin Affinity pulldown (Shimizu et al, 2015) Yes (Wilting et al, 2020) No (Wilting et al, 2020) TBD Erastin Binds to VDAC2; Affinity pulldown (Yagoda et al, 2007) No (Maldonado et al, 2013) No (Maldonado et al, 2013) Increases VDAC2 permeability to NADH (Bauer et al, 2011) Yes (Jacobs, personal communication)…”

Drug Screening and Drug Repositioning as Promising Therapeutic Approaches for Spinal Muscular Atrophy Treatment

“…Most importantly, DR phenotypic screening allowed uncovering novel SMN-independent targets and drug paradigms, such as Olesoxime (see section Mitochondria-Related Pathways). This compound has been identified as potential therapeutic agent for both SMA and ALS (Calder et al, 2016;Swalley, 2020), since it is able to preserve mitochondrial function and protect MNs from degeneration (Calder et al, 2016;Blasco et al, 2018;Rovini et al, 2019). Indeed, a successful repositioning strategy in SMA treatment may be to identify drugs that are currently used to treat other neuromuscular diseases [such as ALS, hereditary spastic paraplegia (HSP) and Duchenne dystrophy (DD) (Patten et al, 2014)]: FDA-approved drugs modulating the pathogenetic pathways shared by these diseases have been proposed for SMA patients, as riluzole (Rilutek ™ or Teglutik ™ ) (see section Neurotransmitters' Modulation), commonly administered for ALS (Calder et al, 2016;Hoolachan et al, 2019;Hensel et al, 2020).…”