Objective/Rationale:
Nurr1 is a nuclear hormone receptor strongly implicated in the growth, maintenance, and survival of dopaminergic neurons, that represents a very promising therapeutic target for Parkinson’s disease (PD). The essential role of Nurr1 in dopaminergic cell development was dramatically demonstrated when these neurons failed to develop in mice lacking the Nurr1 receptor. In addition, Nurr1 limits inflammatory responses in the central nervous system and specifically protects dopaminergic neurons. These observations suggest that Nurr1 might be an excellent therapeutic target for Symptoms & Side Effects and disease-modifying PD drugs.
Project Description:
It is unknown whether Nurr1 acts alone, or in concert with other nuclear receptors to mediate its beneficial effects on dopaminergic neurons. We will develop cell-based functional tests to measure activation of Nurr1 alone or together with other nuclear hormone receptors that can be used to perform high-throughput screens to identify novel Nurr1 activators that could be eventually developed into PD drugs.
Relevance to Diagnosis/Treatment of Parkinson's’s Disease:
Nurr1 activators have great potential as PD drugs as the presence of functional Nurr1 is essential for proper development, function and survival of dopaminergic neurons. There exists a need to determine if ligand-activation of Nurr1 enhances these benefits and discover novel Nurr1 ligands to further explore its therapeutic potential.
Anticipated Outcome:
We believe that clarifying whether Nurr1 acts alone or with other receptors, and identifying activators of Nurr1 will allow us to more fully assess the true therapeutic value of Nurr1 and allow discovery of novel drugs with therapeutic potential for PD.
Final Outcome
We have enabled Bioluminescence Resonance Energy Transfer (BRET) assays to directly examine ligand-induced effects on RXR and Nurr1 homodimers, heterodimers and monomers and profiled a collection of compounds with diverse chemical structures and diverse pharmacological properties. Examples of ligands preferentially activating Nurr1-RXR heterodimers, RXR homodimers, or showing no preference were found. There was no evidence that any of the tested compounds bound directly to Nurr1. Experiments with these same compounds in luciferase reporter gene assays employing RXR, RAR and Nurr1-specific promoter elements generally corroborated the main finding from the BRET assays. A correlation was noted between activation of Nurr1-RXR heterodimers in BRET and neuroprotection of DA neurons in models of PD. These results demonstrate that high-throughput screening (HTS) using the BRET techniques described herin will likely be a useful method to uncover novel chemical scaffolds with a bias toward activating Nurr10RXR heterodimers.