Therapeutic peptide SS-31 modulates membrane binding and aggregation of α-synuclein and restores impaired mitochondrial function
Author(s)
Type
Journal Article
Abstract
Membrane binding and aggregation properties of α-synuclein are closely associated with Parkinson's disease and a class of related syndromes named as synucleinopathy. This study explored the potential of SS-31 (Elamipretide), a therapeutic tetrapeptide with alternating cationic and aromatic residues and known properties of mitochondrial inner membrane binding and oxidative stress reduction, in modulating α-synuclein interaction with the lipid membranes and mitigating the impairment of mitochondrial function induced by α-synuclein oligomers. It was demonstrated by both fluorescence correlation spectroscopy and fluorescence anisotropy that SS-31 displaces both wild-type and N-terminal acetylated α-synuclein from negatively charged small unilamellar vesicles in a dose-dependent manner. Thioflavin-T assay and transmission electron microscopy showed that SS-31 inhibits membrane-induced α-synuclein aggregation and alters the morphology of α-synuclein fibrils. Moreover, MTT assay and Seahorse Mito Stress Test indicated that SS-31 enhances cell viability and restores impaired mitochondrial function in α-synuclein oligomer-treated neuroblastoma cells. Finally, confocal imaging revealed that SS-31 hinders cellular uptake of α-synuclein oligomers, possibly by modifying cell membrane electrostatics. These findings suggest that SS-31 potentially attenuates α-synuclein induced mitochondrial impairment via its interaction with the lipid membranes, justifying further development of a peptide-based intervention against α-synuclein mediated pathology.
Date Issued
2026-06-01
Date Acceptance
2026-05-20
Citation
Chemical Biology and Drug Design, 2026, 107 (6)
ISSN
1747-0277
Publisher
Wiley
Journal / Book Title
Chemical Biology and Drug Design
Volume
107
Issue
6
Copyright Statement
© 2026 The Author(s). Chemical Biology & Drug Design published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Publication Status
Published
Article Number
e70332
Date Publish Online
2026-05-31