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NURR1 in Parkinson disease—from pathogenesis to therapeutic potential

Nature Reviews Neurology volume 9, pages 629–636 (2013)Cite this article

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Abstract

In Parkinson disease (PD), affected midbrain dopamine (DA) neurons lose specific dopaminergic properties before the neurons die. How the phenotype of DA neurons is normally established and the ways in which pathology affects the maintenance of cell identity are, therefore, important considerations. Orphan nuclear receptor NURR1 (NURR1, also known as NR4A2) is involved in the differentiation of midbrain DA neurons, but also has an important role in the adult brain. Emerging evidence indicates that impaired NURR1 function might contribute to the pathogenesis of PD: NURR1 and its transcriptional targets are downregulated in midbrain DA neurons that express high levels of the disease-causing protein α-synuclein. Clinical and experimental data indicate that disrupted NURR1 function contributes to induction of DA neuron dysfunction, which is seen in early stages of PD. The likely involvement of NURR1 in the development and progression of PD makes this protein a potentially interesting target for therapeutic intervention.

Key Points

  • NURR1 and other transcription factors that are essential for the development and specification of midbrain dopamine neurons during development continue to have an important role in the adult brain

  • Deletion of NURR1 in mature dopamine neurons results in progressive pathology, reduction in dopamine neuron markers and motor impairments—recapitulating early features of Parkinson disease

  • Ablation of Nurr1 in adult rodents results in reduced expression of genes associated with mitochondrial function and oxidative phosphorylation, suggesting a role for Nurr1 in the maintenance of midbrain dopamine neurons

  • NURR1 and its transcriptional targets are downregulated in midbrain dopamine neurons that express high levels of the disease-causing protein α-synuclein, as observed in rodent models and patients with Parkinson disease

  • α-Synuclein overexpression results in an almost complete blockade of GDNF trophic signalling and failure of GDNF to protect against α-synuclein-induced toxicity in affected neurons

  • Reduced NURR1 expression might result in induction of dopamine neuron dysfunction as well progression of degenerative changes, which could make this protein a promising therapeutic target

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Figure 1: Summary of NURR1 functional domains, mode of DNA binding and mutations identified in the human NURR1 gene (NR4A2).
Figure 2: The DA neuron functions of NURR1.

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Acknowledgements

We thank members in our laboratories for valuable discussions. This work was supported by grants from the Swedish Research Council via a Linnaeus grant (A. Björklund & T. Perlmann), the Swedish Strategic Research Foundation (A. Björklund & T. Perlmann) and the Michael J. Fox Foundation (A. Björklund & T. Perlmann). We apologize to the authors of the many interesting studies that could not be included in this Review owing to space constraints.

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  1. Department of Experimental Medical Sciences, Wallenberg Neuroscience Centre, Lund University, BMC A11, Lund, 22184, Sweden

    Mickael Decressac & Anders Björklund

  2. Ludwig Institute for Cancer Research, Karolinska Institute, Stockholm, S-171 77, Sweden

    Nikolaos Volakakis & Thomas Perlmann

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All authors researched data for the article, provided substantial discussion of content, contributed to writing the article, and review and/or editing of the manuscript before submission.

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Correspondence to Thomas Perlmann.

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Decressac, M., Volakakis, N., Björklund, A. et al. NURR1 in Parkinson disease—from pathogenesis to therapeutic potential. Nat Rev Neurol 9, 629–636 (2013). https://doi.org/10.1038/nrneurol.2013.209

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