Nurr1 is a nuclear hormone receptor strongly implicated in the growth, maintenance, and survival of dopaminergic neurons. No endogenous Nurr1 ligands have been identified, and Nurr1 may be unable to bind compounds directly. Instead we have found Nurr1 may be targeted indirectly through its binding partners. Using receptors tagged with green fluorescent protein (GFP) and Renilla luciferase to directly monitor activation of Nurr1 alone or with other nuclear hormone receptors, we identified compounds that promote viability of dopamine-containing neurons and selectively promote activation of Nurr1-RXR complexes.
The Nurr1-RXR agonists we discovered were not developed for treating Parkinson’s disease (PD). We will create novel chemical entities based on these Nurr1-RXR agonists that will be optimized for treating PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Drugs that can slow, halt or reverse the progression of PD are desperately needed. Nurr1 is essential for proper development, function and survival of dopaminergic neurons. Thus, drugs that activate Nurr1 have disease modifying potential in PD.
We believe that developing Nurr1-RXR agonists will result in therapeutic agents with disease modifying potential in PD.
Previously we used receptors tagged with green fluorescent protein (GFP) and Renilla luciferase to directly monitor activation of Nurr1 alone or with other nuclear hormone receptors, and identified compounds that selectively promote activation of Nurr1-RXR complexes. We have subsequently shown one of these compounds restores motoric function and viability of DAergic neurons in pre-clinical models lesioned with 6OHDA, and displays trophic actions similar to BDNF in primary cultures of DAergic neurons. These results are consistent with our contention that Nurr1-RXR selective agonists have disease modifying potential in PD.
Work from this program was presented as a poster at The Michael J. Fox Foundation annual PD conference on October 26, 2011.