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

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)alpha in controlling the transcription of Nurr1. Our mRNA analyses followed by different immunoassays clearly indicated that PPAR alpha agonist gemfibrozil strongly upregulated the expression of Nurr1 in wild-type, but not PPAR alpha(-/-), 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 PPAR alpha plasmids confirmed that PPAR alpha 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 PPAR alpha(-/-), mice identifying PPAR alpha as a novel regulator of Nurr1 expression and associated protection of DA neurons.