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García-Yagüe ÁJ, Lastres-Becker I, Stefanis L, et al. α-Synuclein Induces the GSK-3-Mediated Phosphorylation and Degradation of NURR1 and Loss of Dopaminergic Hallmarks. Mol Neurobiol. 2021;58(12):6697-6711doi: 10.1007/s12035-021-02558-9.
García-Yagüe, �. �. J., Lastres-Becker, I., Stefanis, L., Vassilatis, D. K., & Cuadrado, A. (2021). α-Synuclein Induces the GSK-3-Mediated Phosphorylation and Degradation of NURR1 and Loss of Dopaminergic Hallmarks. Molecular neurobiology, 58(12), 6697-6711. https://doi.org/10.1007/s12035-021-02558-9
García-Yagüe, Ángel Juan, et al. "α-Synuclein Induces the GSK-3-Mediated Phosphorylation and Degradation of NURR1 and Loss of Dopaminergic Hallmarks." Molecular neurobiology vol. 58,12 (2021): 6697-6711. doi: https://doi.org/10.1007/s12035-021-02558-9
García-Yagüe ÁJ, Lastres-Becker I, Stefanis L, Vassilatis DK, Cuadrado A. α-Synuclein Induces the GSK-3-Mediated Phosphorylation and Degradation of NURR1 and Loss of Dopaminergic Hallmarks. Mol Neurobiol. 2021 Dec;58(12):6697-6711. doi: 10.1007/s12035-021-02558-9. Epub 2021 Oct 05. PMID: 34609698; PMCID: PMC8639559.
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Mol Neurobiol. 2021 Dec;58(12):6697-6711. doi: 10.1007/s12035-021-02558-9. Epub 2021 Oct 05.

α-Synuclein Induces the GSK-3-Mediated Phosphorylation and Degradation of NURR1 and Loss of Dopaminergic Hallmarks.

Molecular neurobiology

Ángel Juan García-Yagüe, Isabel Lastres-Becker, Leonidas Stefanis, Demetrios K Vassilatis, Antonio Cuadrado

Affiliations

  1. Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain.
  2. Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain.
  3. Instituto de Investigación Sanitaria La Paz (IdiPaz), C/ Arturo Duperier, 4, 28029, Madrid, Spain.
  4. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, Madrid, Spain.
  5. 1St Department of Neurology, Aiginition University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
  6. National and Kapodistrian University of Athens, Athens, Greece.
  7. Center of Clinical Research, Biomedical Research Foundation, Experimental Surgery and Translational Research, Academy of Athens, Athens, Greece.
  8. Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain. [email protected].
  9. Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain. [email protected].
  10. Instituto de Investigación Sanitaria La Paz (IdiPaz), C/ Arturo Duperier, 4, 28029, Madrid, Spain. [email protected].
  11. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, Madrid, Spain. [email protected].

PMID: 34609698 PMCID: PMC8639559 DOI: 10.1007/s12035-021-02558-9

Abstract

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.

© 2021. The Author(s).

Keywords: Dopaminergic neurons; Dopaminergic phenotype; Parkinson’s disease; Transcription

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