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Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau

Amyloid aggregation of α-synuclein (αS) is the hallmark of Parkinson’s disease and other synucleinopathies. Recently, Tau protein, generally associated with Alzheimer’s disease, has been linked to αS pathology and observed to co-localize in αS-rich disease inclusions, although the molecular mechanis...

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Autores principales: Gracia, Pablo, Polanco, David, Tarancón-Díez, Jorge, Serra, Ilenia, Bracci, Maruan, Oroz, Javier, Laurents, Douglas V., García, Inés, Cremades, Nunilo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357037/
https://www.ncbi.nlm.nih.gov/pubmed/35933508
http://dx.doi.org/10.1038/s41467-022-32350-9
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author Gracia, Pablo
Polanco, David
Tarancón-Díez, Jorge
Serra, Ilenia
Bracci, Maruan
Oroz, Javier
Laurents, Douglas V.
García, Inés
Cremades, Nunilo
author_facet Gracia, Pablo
Polanco, David
Tarancón-Díez, Jorge
Serra, Ilenia
Bracci, Maruan
Oroz, Javier
Laurents, Douglas V.
García, Inés
Cremades, Nunilo
author_sort Gracia, Pablo
collection PubMed
description Amyloid aggregation of α-synuclein (αS) is the hallmark of Parkinson’s disease and other synucleinopathies. Recently, Tau protein, generally associated with Alzheimer’s disease, has been linked to αS pathology and observed to co-localize in αS-rich disease inclusions, although the molecular mechanisms for the co-aggregation of both proteins remain elusive. We report here that αS phase-separates into liquid condensates by electrostatic complex coacervation with positively charged polypeptides such as Tau. Condensates undergo either fast gelation or coalescence followed by slow amyloid aggregation depending on the affinity of αS for the poly-cation and the rate of valence exhaustion of the condensate network. By combining a set of advanced biophysical techniques, we have been able to characterize αS/Tau liquid-liquid phase separation and identified key factors that lead to the formation of hetero-aggregates containing both proteins in the interior of the liquid protein condensates.
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spelling pubmed-93570372022-08-08 Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau Gracia, Pablo Polanco, David Tarancón-Díez, Jorge Serra, Ilenia Bracci, Maruan Oroz, Javier Laurents, Douglas V. García, Inés Cremades, Nunilo Nat Commun Article Amyloid aggregation of α-synuclein (αS) is the hallmark of Parkinson’s disease and other synucleinopathies. Recently, Tau protein, generally associated with Alzheimer’s disease, has been linked to αS pathology and observed to co-localize in αS-rich disease inclusions, although the molecular mechanisms for the co-aggregation of both proteins remain elusive. We report here that αS phase-separates into liquid condensates by electrostatic complex coacervation with positively charged polypeptides such as Tau. Condensates undergo either fast gelation or coalescence followed by slow amyloid aggregation depending on the affinity of αS for the poly-cation and the rate of valence exhaustion of the condensate network. By combining a set of advanced biophysical techniques, we have been able to characterize αS/Tau liquid-liquid phase separation and identified key factors that lead to the formation of hetero-aggregates containing both proteins in the interior of the liquid protein condensates. Nature Publishing Group UK 2022-08-06 /pmc/articles/PMC9357037/ /pubmed/35933508 http://dx.doi.org/10.1038/s41467-022-32350-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Gracia, Pablo
Polanco, David
Tarancón-Díez, Jorge
Serra, Ilenia
Bracci, Maruan
Oroz, Javier
Laurents, Douglas V.
García, Inés
Cremades, Nunilo
Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau
title Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau
title_full Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau
title_fullStr Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau
title_full_unstemmed Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau
title_short Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau
title_sort molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357037/
https://www.ncbi.nlm.nih.gov/pubmed/35933508
http://dx.doi.org/10.1038/s41467-022-32350-9
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