دورية أكاديمية
Molecular mechanism of α-synuclein aggregation on lipid membranes revealed.
| العنوان: | Molecular mechanism of α-synuclein aggregation on lipid membranes revealed. |
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| المؤلفون: | Dear AJ; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Teng X; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Ball SR; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Lewin J; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Horne RI; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Clow D; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Stevenson A; Department of Biology, Institute of Biochemistry, ETH Zurich Otto Stern Weg 3 8093 Zurich Switzerland.; Bringing Materials to Life Initiative, ETH Zurich Switzerland., Harper N; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Yahya K; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Yang X; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Brewerton SC; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Thomson J; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Michaels TCT; Department of Biology, Institute of Biochemistry, ETH Zurich Otto Stern Weg 3 8093 Zurich Switzerland.; Bringing Materials to Life Initiative, ETH Zurich Switzerland., Linse S; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com.; Biochemistry and Structural Biology, Lund University Lund Sweden., Knowles TPJ; Yusuf Hamied Department of Chemistry, University of Cambridge Cambridge UK.; Cavendish Laboratory, University of Cambridge Cambridge UK., Habchi J; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com., Meisl G; WaveBreak Therapeutics Ltd, Chemistry of Health Lensfield Road Cambridge CB2 1EW UK georg.meisl@googlemail.com. |
| المصدر: | Chemical science [Chem Sci] 2024 Apr 22; Vol. 15 (19), pp. 7229-7242. Date of Electronic Publication: 2024 Apr 22 (Print Publication: 2024). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Royal Society of Chemistry Country of Publication: England NLM ID: 101545951 Publication Model: eCollection Cited Medium: Print ISSN: 2041-6520 (Print) Linking ISSN: 20416520 NLM ISO Abbreviation: Chem Sci Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: Cambridge, UK : Royal Society of Chemistry, [2010]- |
| مستخلص: | The central hallmark of Parkinson's disease pathology is the aggregation of the α-synuclein protein, which, in its healthy form, is associated with lipid membranes. Purified monomeric α-synuclein is relatively stable in vitro , but its aggregation can be triggered by the presence of lipid vesicles. Despite this central importance of lipids in the context of α-synuclein aggregation, their detailed mechanistic role in this process has not been established to date. Here, we use chemical kinetics to develop a mechanistic model that is able to globally describe the aggregation behaviour of α-synuclein in the presence of DMPS lipid vesicles, across a range of lipid and protein concentrations. Through the application of our kinetic model to experimental data, we find that the reaction is a co-aggregation process involving both protein and lipids and that lipids promote aggregation as much by enabling fibril elongation as by enabling their initial formation. Moreover, we find that the primary nucleation of lipid-protein co-aggregates takes place not on the surface of lipid vesicles in bulk solution but at the air-water and/or plate interfaces, where lipids and proteins are likely adsorbed. Our model forms the basis for mechanistic insights, also in other lipid-protein co-aggregation systems, which will be crucial in the rational design of drugs that inhibit aggregate formation and act at the key points in the α-synuclein aggregation cascade. Competing Interests: All authors except AS were, at the time of their contribution, employees, founders or consultants of WaveBreak Therapeutics. (This journal is © The Royal Society of Chemistry.) |
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| تواريخ الأحداث: | Date Created: 20240517 Latest Revision: 20240518 |
| رمز التحديث: | 20240518 |
| مُعرف محوري في PubMed: | PMC11095391 |
| DOI: | 10.1039/d3sc05661a |
| PMID: | 38756798 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2041-6520 |
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| DOI: | 10.1039/d3sc05661a |