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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/52775
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/52775
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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 Técnicas2025-10-15T15:01:18Zoai: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:34982025-10-15 15:01:18.726CONICET 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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score 13.22299

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