The N-Terminal Region of Nurr1 (a.a 1-31) Is Essential for Its Efficient Degradation by the Ubiquitin Proteasome Pathway

NURR1/NR4A2 is an orphan nuclear receptor that is critical for the development and maintenance of mesencephalic dopaminergic neurons and regulates transcription of genes involved in the function of dopaminergic neurons directly via specific NGFI-B response elements (NBRE). and substantial data support a possible role of Nurr1 in the pathogenesis of Parkinson's disease (PD). Here we show that Nurr1 is degraded by the ubiquitin-proteasome pathway and determined that N-terminal region (a. a 1-31) of Nurr1 is essential for an efficient targeting of Nurr1 to degradation in the cell. Nurr1 Delta 1-31 has a much longer half-life, and as a consequence its steady-state protein levels were higher, than full-length Nurr1 in the cell. Nurr1 Delta 1-31 was as potent as Nurr1 full length in transcriptional luciferase reporter assays after normalization with the corresponding steady-state protein expression levels, either in trans-activation of NBRE or trans-repression of iNOS (inducible NO synthase) reporters. These results suggest that Nurr1 Delta 1-31, because of longer persistence in the cell, can be a good candidate for gene and cell therapies in the treatment of PD.