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Activation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic Neurons

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Abstract

Nuclear receptor related 1 protein (Nurr1) is an important transcription factor required for differentiation and maintenance of midbrain dopaminergic (DA) neurons. Since decrease in Nurr1 function either due to diminished expression or rare mutation is associated with Parkinson’s disease (PD), upregulation of Nurr1 may be beneficial for PD. However, such mechanisms are poorly understood. This study underlines the importance of peroxisome proliferator-activated receptor (PPAR)α in controlling the transcription of Nurr1. Our mRNA analyses followed by different immunoassays clearly indicated that PPARα agonist gemfibrozil strongly upregulated the expression of Nurr1 in wild-type, but not PPARα−/−, DA neurons. Moreover, identification of conserved PPRE in the promoter of Nurr1 gene followed by chromatin immunoprecipitation analysis, PPRE luciferase assay, and manipulation of Nurr1 gene by viral transduction of different PPARα plasmids confirmed that PPARα was indeed involved in the expression of Nurr1. Finally, oral administration of gemfibrozil increased Nurr1 expression in vivo in nigra of wild-type, but not PPARα−/−, mice identifying PPARα as a novel regulator of Nurr1 expression and associated protection of DA neurons.

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Funding

This study was supported by a merit award from Veteran Affairs (I01BX003033) and a grant (NS083054) from NIH.

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Authors and Affiliations

  1. Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison St, Suite Cohn 310, Chicago, IL, 60612, USA

    Carl G. Gottschalk, Avik Roy, Malabendu Jana, Madhuchhanda Kundu & Kalipada Pahan

  2. Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA

    Avik Roy, Malabendu Jana & Kalipada Pahan

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  1. Carl G. Gottschalk
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  2. Avik Roy
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  3. Malabendu Jana
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  5. Kalipada Pahan
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Correspondence to Kalipada Pahan.

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Animal maintenance and experimental protocols were approved by the Rush University Animal Care Committee. All animal procedures were conducted in accordance with the Rush University IUCUC protocol (15-056).

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Gottschalk, C.G., Roy, A., Jana, M. et al. Activation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic Neurons. Mol Neurobiol 56, 7872–7887 (2019). https://doi.org/10.1007/s12035-019-01649-y

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