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

Identificadores del recurso

Molecular Neurobiology 58.12 (2021): 6697–6711

1559-1182

http://hdl.handle.net/10486/700738

10.1007/s12035-021-02558-9

6697

6711

Procedència

(Biblos-e Archivo)

Fitxa

Títol:: α-Synuclein induces the GSK-3-mediated phosphorylation and degradation of NURR1 and loss of dopaminergic hallmarks
Tema:: Dopaminergic neurons; Dopaminergic phenotype; Parkinson’s disease; Transcription; Medicina
Descripció:: 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; This 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.)
Idioma:: English
Relació:: Gobierno de España. PID2019-110061RB-I00; Gobierno de España. PID2019-105600RB-I00; Comunidad de Madrid. B2017/BMD-3827/NRF24AD-CM; Comunidad de Madrid. B2017/BMD-3813/ELA-MADRID-CM
Autor/Productor:: García Yagüe, Ángel Juan; Lastres Becker, Isabel; Stefanis, Leonidas; Vassilatis, Demetrios K.; Cuadrado Pastor, Antonio
Editor:: Springer
Otros colaboradores/productores:: UAM. Departamento de Bioquímica
Drets:: open access
Data:: 2021-10-05
Tipo de recurso:: journal article; info:eu-repo/semantics/publishedVersion
Format:: application/pdf

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