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bioRxiv · 10.1101/2022.04.07.487541

Restricting α-Synuclein Transport into Mitochondria by Inhibition of α-Synuclein-VDAC Complexation as a Potential Therapeutic Target for Parkinson's Disease Treatment

Rajendran, M.·Queralt-Martin, M.·Gurnev, P. A.·Rosencrans, W. M.·Rovini, A.·Jacobs, D.·Abrantes, K.·Hoogerheide, D. P.·Bezrukov, S. M.·Rostovtseva, T. K.
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Abstract

Involvement of alpha-synuclein (Syn) in Parkinsons disease (PD) is complicated and difficult to trace on cellular and molecular levels. Recently we established that Syn can regulate mitochondrial function by voltage-activated complexation with the Voltage-Dependent Anion Channel (VDAC) of the outer mitochondrial membrane. When complexed with Syn, the VDAC pore is partially blocked, reducing the transport of ATP/ADP and other metabolites. Further, Syn can translocate into the mitochondria through VDAC, where it interferes with mitochondrial respiration. Recruitment of Syn to the VDAC-containing lipid membrane appears to be a crucial prerequisite for both the blockage and translocation processes. Here we report an inhibitory effect of HK2p, a small membrane-binding peptide from the mitochondria-targeting N-terminus of hexokinase 2, on the Syn membrane binding, and hence on Syn complex formation with VDAC and translocation through it. In electrophysiology experiments, addition of HK2p at micromolar concentrations to the same side of the membrane as Syn results in dramatic reduction of the frequency of blockage events in a concentration-dependent manner, reporting on complexation inhibition. Using two complementary methods of measuring protein-membrane binding, bilayer overtone analysis and fluorescence correlation spectroscopy, we found that HK2p induces detachment of Syn from lipid membranes. Experiments with live HeLa cells using proximity ligation assay confirmed that HK2p impedes Syn entry into mitochondria. Our results demonstrate that it is possible to regulate Syn-VDAC complexation by a rationally designed peptide, thus suggesting new avenues in the search for peptide therapeutics to alleviate Syn mitochondrial toxicity in PD and other synucleinopathies.

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Rajendran, M., Queralt-Martin, M., Gurnev, P. A., Rosencrans, W. M., Rovini, A., Jacobs, D., Abrantes, K., Hoogerheide, D. P., Bezrukov, S. M., Rostovtseva, T. K.. 2022-04-08. Restricting α-Synuclein Transport into Mitochondria by Inhibition of α-Synuclein-VDAC Complexation as a Potential Therapeutic Target for Parkinson's Disease Treatment. https://doi.org/10.1101/2022.04.07.487541

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