Single-vesicle imaging reveals lipid-selective and stepwise membrane disruption by monomeric α-synuclein
| Autor: | Sandra Rocha, Fredrik Höök, Björn Agnarsson, Pernilla Wittung-Stafshede, Vladimir P. Zhdanov, Jonas K. Hannestad |
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| Rok vydání: | 2020 |
| Předmět: |
Lipid Bilayers
Nerve Tissue Proteins Context (language use) Protein aggregation Synaptic vesicle Membrane Lipids chemistry.chemical_compound α-synuclein Humans membrane interaction Inner mitochondrial membrane Neurons Phosphatidylglycerol Membranes Multidisciplinary Chemistry Vesicle Parkinson Disease Phosphatidylglycerols Phosphatidylserine Biological Sciences Fluoresceins Kinetics Biophysics and Computational Biology single-vesicle scattering Membrane lipid vesicle Physical Sciences alpha-Synuclein Biophysics Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1914670117 |
| Popis: | Significance Neurodegenerative diseases are increasing among the world's population, but there are no cures. These disorders all involve proteins that assemble into amyloid fibers which results in brain cell death. Evidence suggests that association of these proteins with lipid membranes is crucial for both functional and pathological roles. In Parkinson's disease, the involved protein, α-synuclein, is thought to function in trafficking of lipid vesicles in the brain. In search of mechanistic origins, increasing focus is put on identifying neurotoxic reactions induced by membrane interactions. To contribute new clues to this question, we here employed a new surface-sensitive scattering microscopy technique. With this approach, we discovered that α-synuclein perturbs vesicles in a stepwise and lipid-dependent fashion already at very low protein coverage. The interaction of the neuronal protein α-synuclein with lipid membranes appears crucial in the context of Parkinson’s disease, but the underlying mechanistic details, including the roles of different lipids in pathogenic protein aggregation and membrane disruption, remain elusive. Here, we used single-vesicle resolution fluorescence and label-free scattering microscopy to investigate the interaction kinetics of monomeric α-synuclein with surface-tethered vesicles composed of different negatively charged lipids. Supported by a theoretical model to account for structural changes in scattering properties of surface-tethered lipid vesicles, the data demonstrate stepwise vesicle disruption and asymmetric membrane deformation upon α-synuclein binding to phosphatidylglycerol vesicles at protein concentrations down to 10 nM (∼100 proteins per vesicle). In contrast, phosphatidylserine vesicles were only marginally affected. These insights into structural consequences of α-synuclein interaction with lipid vesicles highlight the contrasting roles of different anionic lipids, which may be of mechanistic relevance for both normal protein function (e.g., synaptic vesicle binding) and dysfunction (e.g., mitochondrial membrane interaction). |
| Databáze: | OpenAIRE |
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