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Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein
dc.contributor.author | Cremades, Nunilo | |
dc.contributor.author | Orte Gutiérrez, Ángel | |
dc.date.accessioned | 2020-06-22T10:53:42Z | |
dc.date.available | 2020-06-22T10:53:42Z | |
dc.date.issued | 2012-05-25 | |
dc.identifier.citation | Cremades, N., Cohen, S. I., Deas, E., Abramov, A. Y., Chen, A. Y., Orte, A., ... & Bertoncini, C. W. (2012). Direct observation of the interconversion of normal and toxic forms of α-synuclein. Cell, 149(5), 1048-1059. [https://doi.org/10.1016/j.cell.2012.03.037] | es_ES |
dc.identifier.uri | http://hdl.handle.net/10481/62603 | |
dc.description | We are grateful to Francisco Mateo and Priyanka Narayan for their helpful comments and discussions. N.C. is the recipient of a Human Frontier Science Program Long-term Fellowship (LT000795/2009). S.I.A.C. is supported by a Schiff Foundation Scholarship, A.O. acknowledges an ERG from the EU 7th FP, A.Y.C. was supported by a Gates Cambridge Scholarship, and M. S. was supported by a FEBS Fellowship. F.A.A. was recipient of a PhD Fellowship from the Italian Ministry of Education, University and Research, and C.W.B. is the recipient of a FP7 Marie Curie IEF grant. E.D., A.Y.A., and N.W.W. are supported by the Wellcome/MRC Parkinson's Disease Consortium grant to UCL/IoN, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee (grant number WT089698). C.M.D. and D.K. acknowledge with gratitude support from the Augustus Newman Foundation, the Wellcome Trust, the Leverhulme Trust, BBSRC (BB/E019927/1), the European Commission (project LSHM-CT-2006-037525), the Medical Research Council (UK), and the Engineering and Physical Sciences Research Council. | es_ES |
dc.description.abstract | Here, we use single-molecule techniques to study the aggregation of α-synuclein, the protein whose misfolding and deposition is associated with Parkinson’s disease. We identify a conformational change from the initially formed oligomers to stable, more compact proteinase-K-resistant oligomers as the key step that leads ultimately to fibril formation. The oligomers formed as a result of the structural conversion generate much higher levels of oxidative stress in rat primary neurons than do the oligomers formed initially, showing that they are more damaging to cells. The structural conversion is remarkably slow, indicating a high kinetic barrier for the conversion and suggesting that there is a significant period of time for the cellular protective machinery to operate and potentially for therapeutic intervention, prior to the onset of cellular damage. In the absence of added soluble protein, the assembly process is reversed and fibrils disaggregate to form stable oligomers, hence acting as a source of cytotoxic species. | es_ES |
dc.description.sponsorship | Human Frontier Science Program LT000795/2009 | es_ES |
dc.description.sponsorship | Schiff Foundation | es_ES |
dc.description.sponsorship | European Union (EU) | es_ES |
dc.description.sponsorship | Gates Cambridge Scholarship | es_ES |
dc.description.sponsorship | FEBS Fellowship | es_ES |
dc.description.sponsorship | Italian Ministry of Education | es_ES |
dc.description.sponsorship | University and Research | es_ES |
dc.description.sponsorship | Wellcome/MRC Parkinson's Disease Consortium | es_ES |
dc.description.sponsorship | University of Sheffield | es_ES |
dc.description.sponsorship | MRC Protein Phosphorylation Unit at the University of Dundee WT089698 | es_ES |
dc.description.sponsorship | Augustus Newman Foundation | es_ES |
dc.description.sponsorship | Wellcome Trust | es_ES |
dc.description.sponsorship | Leverhulme Trust | es_ES |
dc.description.sponsorship | Medical Research Council UK (MRC) | es_ES |
dc.description.sponsorship | Engineering & Physical Sciences Research Council (EPSRC) | es_ES |
dc.description.sponsorship | Biotechnology and Biological Sciences Research Council (BBSRC) BB/E019927/1 | es_ES |
dc.description.sponsorship | European Commission Joint Research Centre LSHM-CT-2006-037525 | es_ES |
dc.description.sponsorship | Biotechnology and Biological Sciences Research Council (BBSRC) BB/E019927/1 | es_ES |
dc.description.sponsorship | Medical Research Council UK (MRC) MC_G1000734 MC_G1000735 | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.rights | Atribución 3.0 España | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.title | Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein | es_ES |
dc.type | journal article | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.identifier.doi | 10.1016/j.cell.2012.03.037 | |
dc.type.hasVersion | VoR | es_ES |