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Parkinson's disease‐linked V15A mutation facilitates α‐synuclein aggregation by reducing membrane affinity
Parkinson's disease can manifest either as a sporadic form, which is common, or as an inherited autosomal dominant trait resulting from missense mutations. Recently, the novel α‐synuclein variant V15A was identified in two Caucasian and two Japanese families with Parkinson's disease. Using...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10357493/ https://www.ncbi.nlm.nih.gov/pubmed/37358478 http://dx.doi.org/10.1002/pro.4693 |
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author | Buratti, Fiamma A. Fernández, Claudio Oscar Zweckstetter, Markus |
author_facet | Buratti, Fiamma A. Fernández, Claudio Oscar Zweckstetter, Markus |
author_sort | Buratti, Fiamma A. |
collection | PubMed |
description | Parkinson's disease can manifest either as a sporadic form, which is common, or as an inherited autosomal dominant trait resulting from missense mutations. Recently, the novel α‐synuclein variant V15A was identified in two Caucasian and two Japanese families with Parkinson's disease. Using a combination of NMR spectroscopy, membrane binding assays and aggregation assays we show that the V15A mutation does not strongly perturb the conformational ensemble of monomeric α‐synuclein in solution, but weakens its affinity for membranes. Attenuated membrane binding raises the concentration of the aggregation‐prone disordered α‐synuclein in solution, allowing only the V15A variant but not wild‐type α‐synuclein to form amyloid fibrils in the presence of liposomes. These findings, together with earlier research on other missense mutations of α‐synuclein, suggest that maintaining a balance between membrane‐bound and free aggregation‐competent α‐synuclein is critical in α‐synucleinopathies. |
format | Online Article Text |
id | pubmed-10357493 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley & Sons, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-103574932023-08-01 Parkinson's disease‐linked V15A mutation facilitates α‐synuclein aggregation by reducing membrane affinity Buratti, Fiamma A. Fernández, Claudio Oscar Zweckstetter, Markus Protein Sci Research Note Parkinson's disease can manifest either as a sporadic form, which is common, or as an inherited autosomal dominant trait resulting from missense mutations. Recently, the novel α‐synuclein variant V15A was identified in two Caucasian and two Japanese families with Parkinson's disease. Using a combination of NMR spectroscopy, membrane binding assays and aggregation assays we show that the V15A mutation does not strongly perturb the conformational ensemble of monomeric α‐synuclein in solution, but weakens its affinity for membranes. Attenuated membrane binding raises the concentration of the aggregation‐prone disordered α‐synuclein in solution, allowing only the V15A variant but not wild‐type α‐synuclein to form amyloid fibrils in the presence of liposomes. These findings, together with earlier research on other missense mutations of α‐synuclein, suggest that maintaining a balance between membrane‐bound and free aggregation‐competent α‐synuclein is critical in α‐synucleinopathies. John Wiley & Sons, Inc. 2023-08-01 /pmc/articles/PMC10357493/ /pubmed/37358478 http://dx.doi.org/10.1002/pro.4693 Text en © 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Note Buratti, Fiamma A. Fernández, Claudio Oscar Zweckstetter, Markus Parkinson's disease‐linked V15A mutation facilitates α‐synuclein aggregation by reducing membrane affinity |
title | Parkinson's disease‐linked V15A mutation facilitates α‐synuclein aggregation by reducing membrane affinity |
title_full | Parkinson's disease‐linked V15A mutation facilitates α‐synuclein aggregation by reducing membrane affinity |
title_fullStr | Parkinson's disease‐linked V15A mutation facilitates α‐synuclein aggregation by reducing membrane affinity |
title_full_unstemmed | Parkinson's disease‐linked V15A mutation facilitates α‐synuclein aggregation by reducing membrane affinity |
title_short | Parkinson's disease‐linked V15A mutation facilitates α‐synuclein aggregation by reducing membrane affinity |
title_sort | parkinson's disease‐linked v15a mutation facilitates α‐synuclein aggregation by reducing membrane affinity |
topic | Research Note |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10357493/ https://www.ncbi.nlm.nih.gov/pubmed/37358478 http://dx.doi.org/10.1002/pro.4693 |
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