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...
| Autores: | , , , , |
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| 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 |
| Sumario: | 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 |
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