Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites
- Autores
- Binolfi, Andrés; Limatola, Antonio; Verzini, Silvia; Kosten, Jonas; Theillet, Francois Xavier; May Rose, Honor; Bekei, Beata; Stuiver, Marchel; Van Rossum, Marleen; Selenko, Philipp
- Año de publicación
- 2016
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Cellular oxidative stress serves as a common denominator in many neurodegenerative disorders, including Parkinson's disease. Here we use in-cell NMR spectroscopy to study the fate of the oxidation-damaged Parkinsonâ (tm) s disease protein alpha-synuclein (α-Syn) in non-neuronal and neuronal mammalian cells. Specifically, we deliver methionine-oxidized, isotope-enriched α-Syn into cultured cells and follow intracellular protein repair by endogenous enzymes at atomic resolution. We show that N-terminal α-Syn methionines Met1 and Met5 are processed in a stepwise manner, with Met5 being exclusively repaired before Met1. By contrast, C-terminal methionines Met116 and Met127 remain oxidized and are not targeted by cellular enzymes. In turn, persisting oxidative damage in the C-terminus of α-Syn diminishes phosphorylation of Tyr125 by Fyn kinase, which ablates the necessary priming event for Ser129 modification by CK1. These results establish that oxidative stress can lead to the accumulation of chemically and functionally altered α-Syn in cells.
Fil: Binolfi, Andrés. Leibniz Institute of Molecular Pharmacology; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina
Fil: Limatola, Antonio. Leibniz Institute of Molecular Pharmacology; Alemania. Università degli Studi di Napoli Federico II; Italia
Fil: Verzini, Silvia. Leibniz Institute of Molecular Pharmacology; Alemania
Fil: Kosten, Jonas. Leibniz Institute of Molecular Pharmacology; Alemania
Fil: Theillet, Francois Xavier. Leibniz Institute of Molecular Pharmacology; Alemania. Centre National de la Recherche Scientifique; Francia. Université Paris Sud; Francia
Fil: May Rose, Honor. Leibniz Institute of Molecular Pharmacology; Alemania
Fil: Bekei, Beata. Leibniz Institute of Molecular Pharmacology; Alemania
Fil: Stuiver, Marchel. Leibniz Institute of Molecular Pharmacology; Alemania
Fil: Van Rossum, Marleen. Leibniz Institute of Molecular Pharmacology; Alemania
Fil: Selenko, Philipp. Leibniz Institute of Molecular Pharmacology; Alemania - Materia
-
alpha-synuclein
Methionine oxidation
Phosphorylation
NMR
Parkinson´s disease - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/52775
Ver los metadatos del registro completo
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Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sitesBinolfi, AndrésLimatola, AntonioVerzini, SilviaKosten, JonasTheillet, Francois XavierMay Rose, HonorBekei, BeataStuiver, MarchelVan Rossum, MarleenSelenko, Philippalpha-synucleinMethionine oxidationPhosphorylationNMRParkinson´s diseasehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cellular oxidative stress serves as a common denominator in many neurodegenerative disorders, including Parkinson's disease. Here we use in-cell NMR spectroscopy to study the fate of the oxidation-damaged Parkinsonâ (tm) s disease protein alpha-synuclein (α-Syn) in non-neuronal and neuronal mammalian cells. Specifically, we deliver methionine-oxidized, isotope-enriched α-Syn into cultured cells and follow intracellular protein repair by endogenous enzymes at atomic resolution. We show that N-terminal α-Syn methionines Met1 and Met5 are processed in a stepwise manner, with Met5 being exclusively repaired before Met1. By contrast, C-terminal methionines Met116 and Met127 remain oxidized and are not targeted by cellular enzymes. In turn, persisting oxidative damage in the C-terminus of α-Syn diminishes phosphorylation of Tyr125 by Fyn kinase, which ablates the necessary priming event for Ser129 modification by CK1. These results establish that oxidative stress can lead to the accumulation of chemically and functionally altered α-Syn in cells.Fil: Binolfi, Andrés. Leibniz Institute of Molecular Pharmacology; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; ArgentinaFil: Limatola, Antonio. Leibniz Institute of Molecular Pharmacology; Alemania. Università degli Studi di Napoli Federico II; ItaliaFil: Verzini, Silvia. Leibniz Institute of Molecular Pharmacology; AlemaniaFil: Kosten, Jonas. Leibniz Institute of Molecular Pharmacology; AlemaniaFil: Theillet, Francois Xavier. Leibniz Institute of Molecular Pharmacology; Alemania. Centre National de la Recherche Scientifique; Francia. Université Paris Sud; FranciaFil: May Rose, Honor. Leibniz Institute of Molecular Pharmacology; AlemaniaFil: Bekei, Beata. Leibniz Institute of Molecular Pharmacology; AlemaniaFil: Stuiver, Marchel. Leibniz Institute of Molecular Pharmacology; AlemaniaFil: Van Rossum, Marleen. Leibniz Institute of Molecular Pharmacology; AlemaniaFil: Selenko, Philipp. Leibniz Institute of Molecular Pharmacology; AlemaniaNature2016-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/52775Binolfi, Andrés; Limatola, Antonio; Verzini, Silvia; Kosten, Jonas; Theillet, Francois Xavier; et al.; Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites; Nature; Nature Communications; 7; 1-2016; 1-10; 102512041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.nature.com/articles/ncomms10251info:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms10251info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737712/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:04:39Zoai:ri.conicet.gov.ar:11336/52775instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:04:39.55CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites |
title |
Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites |
spellingShingle |
Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites Binolfi, Andrés alpha-synuclein Methionine oxidation Phosphorylation NMR Parkinson´s disease |
title_short |
Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites |
title_full |
Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites |
title_fullStr |
Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites |
title_full_unstemmed |
Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites |
title_sort |
Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites |
dc.creator.none.fl_str_mv |
Binolfi, Andrés Limatola, Antonio Verzini, Silvia Kosten, Jonas Theillet, Francois Xavier May Rose, Honor Bekei, Beata Stuiver, Marchel Van Rossum, Marleen Selenko, Philipp |
author |
Binolfi, Andrés |
author_facet |
Binolfi, Andrés Limatola, Antonio Verzini, Silvia Kosten, Jonas Theillet, Francois Xavier May Rose, Honor Bekei, Beata Stuiver, Marchel Van Rossum, Marleen Selenko, Philipp |
author_role |
author |
author2 |
Limatola, Antonio Verzini, Silvia Kosten, Jonas Theillet, Francois Xavier May Rose, Honor Bekei, Beata Stuiver, Marchel Van Rossum, Marleen Selenko, Philipp |
author2_role |
author author author author author author author author author |
dc.subject.none.fl_str_mv |
alpha-synuclein Methionine oxidation Phosphorylation NMR Parkinson´s disease |
topic |
alpha-synuclein Methionine oxidation Phosphorylation NMR Parkinson´s disease |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Cellular oxidative stress serves as a common denominator in many neurodegenerative disorders, including Parkinson's disease. Here we use in-cell NMR spectroscopy to study the fate of the oxidation-damaged Parkinsonâ (tm) s disease protein alpha-synuclein (α-Syn) in non-neuronal and neuronal mammalian cells. Specifically, we deliver methionine-oxidized, isotope-enriched α-Syn into cultured cells and follow intracellular protein repair by endogenous enzymes at atomic resolution. We show that N-terminal α-Syn methionines Met1 and Met5 are processed in a stepwise manner, with Met5 being exclusively repaired before Met1. By contrast, C-terminal methionines Met116 and Met127 remain oxidized and are not targeted by cellular enzymes. In turn, persisting oxidative damage in the C-terminus of α-Syn diminishes phosphorylation of Tyr125 by Fyn kinase, which ablates the necessary priming event for Ser129 modification by CK1. These results establish that oxidative stress can lead to the accumulation of chemically and functionally altered α-Syn in cells. Fil: Binolfi, Andrés. Leibniz Institute of Molecular Pharmacology; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina Fil: Limatola, Antonio. Leibniz Institute of Molecular Pharmacology; Alemania. Università degli Studi di Napoli Federico II; Italia Fil: Verzini, Silvia. Leibniz Institute of Molecular Pharmacology; Alemania Fil: Kosten, Jonas. Leibniz Institute of Molecular Pharmacology; Alemania Fil: Theillet, Francois Xavier. Leibniz Institute of Molecular Pharmacology; Alemania. Centre National de la Recherche Scientifique; Francia. Université Paris Sud; Francia Fil: May Rose, Honor. Leibniz Institute of Molecular Pharmacology; Alemania Fil: Bekei, Beata. Leibniz Institute of Molecular Pharmacology; Alemania Fil: Stuiver, Marchel. Leibniz Institute of Molecular Pharmacology; Alemania Fil: Van Rossum, Marleen. Leibniz Institute of Molecular Pharmacology; Alemania Fil: Selenko, Philipp. Leibniz Institute of Molecular Pharmacology; Alemania |
description |
Cellular oxidative stress serves as a common denominator in many neurodegenerative disorders, including Parkinson's disease. Here we use in-cell NMR spectroscopy to study the fate of the oxidation-damaged Parkinsonâ (tm) s disease protein alpha-synuclein (α-Syn) in non-neuronal and neuronal mammalian cells. Specifically, we deliver methionine-oxidized, isotope-enriched α-Syn into cultured cells and follow intracellular protein repair by endogenous enzymes at atomic resolution. We show that N-terminal α-Syn methionines Met1 and Met5 are processed in a stepwise manner, with Met5 being exclusively repaired before Met1. By contrast, C-terminal methionines Met116 and Met127 remain oxidized and are not targeted by cellular enzymes. In turn, persisting oxidative damage in the C-terminus of α-Syn diminishes phosphorylation of Tyr125 by Fyn kinase, which ablates the necessary priming event for Ser129 modification by CK1. These results establish that oxidative stress can lead to the accumulation of chemically and functionally altered α-Syn in cells. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-01 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/52775 Binolfi, Andrés; Limatola, Antonio; Verzini, Silvia; Kosten, Jonas; Theillet, Francois Xavier; et al.; Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites; Nature; Nature Communications; 7; 1-2016; 1-10; 10251 2041-1723 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/52775 |
identifier_str_mv |
Binolfi, Andrés; Limatola, Antonio; Verzini, Silvia; Kosten, Jonas; Theillet, Francois Xavier; et al.; Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites; Nature; Nature Communications; 7; 1-2016; 1-10; 10251 2041-1723 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/http://www.nature.com/articles/ncomms10251 info:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms10251 info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737712/ |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Nature |
publisher.none.fl_str_mv |
Nature |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844613874539560960 |
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13.070432 |