Objective/Rationale:
Transcription factors are nuclear proteins that regulate gene expression. They are likely to play an important role in long-term molecular maladaptive processes such as those occurring in levodopa-induced dyskinesias. We have previously shown that two transcription factors of the nuclear receptor family, Nur77 and Retinoid X Receptor (RXR), are associated with dopamine drug-induced abnormal movements. The general objective of the proposal is to demonstrate that Nur77 and RXR can be targeted to reduce levodopa-induced dyskinesias.
Project Description:
To demonstrate the role of Nur77, we will perform viral-mediated gene transfer to over expressed Nur77 in the striatum in a preclinical model of Parkinson’s disease treated with levodopa. Levodopa-induced dyskinesias will be evaluated using the rotational response, limb use asymmetry (cylinder test) and Abnormal Involuntary Movements (AIMs) rating scale. To investigate the role of RXR, systemic administrations of synthetic RXR agonists in parkinsonian preclinical models will be performed. To confirm that both heterodimer partners (Nur77/RXR as a transcriptional complex) are necessary, we will investigate the effect of RXR agonists in a newly developed Nur77 preclinical model bearing a lesion of dopamine producing neurons.
Relevance to Diagnosis/Treatment of Parkinson’s Disease: Previous observations from our team strongly support that the Nur77/RXR transcriptional complex, through the action of RXR agonists, may represent an interesting and selective target for therapeutic interventions associated with Parkinson’s disease treatment. Indeed, the restricted distribution of RXR in dopamine-associated brain areas indicates that the transcriptional complex form by Nur77 and RXR may represent a selective target for the brain dopamine system with limited effects in the periphery.
Anticipated Outcome:
After the completion of this research project, we should have demonstrated the proof-of-concept that the Nur77/RXR complex is a potential target to reduce levodopa-induced dyskinesias.
Final Outcome
We have previously shown that the transcription factor of the nuclear receptor family, Nur77 (Nr4a1), is strongly up regulated by L-Dopa treatment in various models of Parkinson’s disease. However, its role in L-dopa-induced effects remained unknown. We demonstrated that inactivation of this gene in a newly developed transgenic pre-clinical model strongly reduced L-Dopa-induced dyskinesia, whereas its overexpression in the striatum of wild type or in transgenic pre-clinical models (gene rescue), using a virally driven gene delivery system, exacerbated dyskinesia. This transcription factor is a nuclear receptor protein that modulates the expression of sets of genes in cells. Thus, by reducing Nur77-dependent transcriptional activity, we might be able to restore gene expression patterns altered during prolonged L-dopa treatment and which lead to abnormal involuntary movements.