α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarks

In Parkinson’s disease, the dysfunction of the dopaminergic nigrostriatal tract involves the loss of function of dopaminergic neurons of the substantia nigra pars compacta followed by death of these neurons. The functional recovery of these neurons requires a deep knowledge of the molecules that mai...

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Detalles Bibliográficos
Autores: García Yagüe, Ángel Juan, Lastres Becker, Isabel, Stefanis, Leonidas, Vassilatis, Demetrios K., Cuadrado Pastor, Antonio
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:IAPH
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/700738
Acceso en línea:http://hdl.handle.net/10486/700738
https://dx.doi.org/10.1007/s12035-021-02558-9
Access Level:acceso abierto
Palabra clave:Dopaminergic neurons
Dopaminergic phenotype
Parkinson’s disease
Transcription
Medicina
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spelling α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarksGarcía Yagüe, Ángel JuanLastres Becker, IsabelStefanis, LeonidasVassilatis, Demetrios K.Cuadrado Pastor, AntonioDopaminergic neuronsDopaminergic phenotypeParkinson’s diseaseTranscriptionMedicinaIn Parkinson’s disease, the dysfunction of the dopaminergic nigrostriatal tract involves the loss of function of dopaminergic neurons of the substantia nigra pars compacta followed by death of these neurons. The functional recovery of these neurons requires a deep knowledge of the molecules that maintain the dopaminergic phenotype during adulthood and the mechanisms that subvert their activity. Previous studies have shown that transcription factor NURR1, involved in differentiation and maintenance of the dopaminergic phenotype, is downregulated by α-synuclein (α-SYN). In this study, we provide a mechanistic explanation to this finding by connecting α-SYN-induced activation of glycogen synthase kinase-3 (GSK-3) with NURR1 phosphorylation followed by proteasomal degradation. The use of sequential deletion mutants and single point mutants of NURR1 allowed the identification of a domain comprising amino acids 123-PSSPPTPSTPS-134 that is targeted by GSK-3 and leads to subsequent ubiquitination and proteasome degradation. This study provides a detailed analysis of the regulation of NURR1 stability by phosphorylation in synucleinopathies such as Parkinson’s diseaseThis study was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) (grant PID2019-110061RB-I00 for A.C and PID2019-105600RB-I00 for I.L.B.) and The Autonomous Community of Madrid (grant B2017/ BMD-3827 for A.C. and B2017/BMD-3813 for I.L.B.)SpringerDepartamento de BioquímicaFacultad de Medicina20212021-10-05research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/700738https://dx.doi.org/10.1007/s12035-021-02558-9reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:IAPHInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7007382026-06-23T12:46:27Z
dc.title.none.fl_str_mv α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarks
title α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarks
spellingShingle α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarks
García Yagüe, Ángel Juan
Dopaminergic neurons
Dopaminergic phenotype
Parkinson’s disease
Transcription
Medicina
title_short α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarks
title_full α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarks
title_fullStr α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarks
title_full_unstemmed α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarks
title_sort α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarks
dc.creator.none.fl_str_mv García Yagüe, Ángel Juan
Lastres Becker, Isabel
Stefanis, Leonidas
Vassilatis, Demetrios K.
Cuadrado Pastor, Antonio
author García Yagüe, Ángel Juan
author_facet García Yagüe, Ángel Juan
Lastres Becker, Isabel
Stefanis, Leonidas
Vassilatis, Demetrios K.
Cuadrado Pastor, Antonio
author_role author
author2 Lastres Becker, Isabel
Stefanis, Leonidas
Vassilatis, Demetrios K.
Cuadrado Pastor, Antonio
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Bioquímica
Facultad de Medicina
dc.subject.none.fl_str_mv Dopaminergic neurons
Dopaminergic phenotype
Parkinson’s disease
Transcription
Medicina
topic Dopaminergic neurons
Dopaminergic phenotype
Parkinson’s disease
Transcription
Medicina
description In Parkinson’s disease, the dysfunction of the dopaminergic nigrostriatal tract involves the loss of function of dopaminergic neurons of the substantia nigra pars compacta followed by death of these neurons. The functional recovery of these neurons requires a deep knowledge of the molecules that maintain the dopaminergic phenotype during adulthood and the mechanisms that subvert their activity. Previous studies have shown that transcription factor NURR1, involved in differentiation and maintenance of the dopaminergic phenotype, is downregulated by α-synuclein (α-SYN). In this study, we provide a mechanistic explanation to this finding by connecting α-SYN-induced activation of glycogen synthase kinase-3 (GSK-3) with NURR1 phosphorylation followed by proteasomal degradation. The use of sequential deletion mutants and single point mutants of NURR1 allowed the identification of a domain comprising amino acids 123-PSSPPTPSTPS-134 that is targeted by GSK-3 and leads to subsequent ubiquitination and proteasome degradation. This study provides a detailed analysis of the regulation of NURR1 stability by phosphorylation in synucleinopathies such as Parkinson’s disease
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-10-05
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/700738
https://dx.doi.org/10.1007/s12035-021-02558-9
url http://hdl.handle.net/10486/700738
https://dx.doi.org/10.1007/s12035-021-02558-9
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:IAPH
instname_str IAPH
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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