Funded Studies
Objective/Rationale:
Studies in PD patients have shown that increased cellular levels of α-syn are associated with reduced levels of Nurr1, and that mutations in the Nurr1 gene that have been linked to the development of PD. These observations highlight Nurr1 as a promising novel target for neuroprotective therapy in PD, and that drugs designed to activate Nurr1 function may hold particular promise. Nurr1 belongs to a nuclear receptor family that can be targeted by small lipophilic ligands, and since Nurr1 can form heterodimers with RXR it seems possible that RXR ligands may be used to modulate also Nurr1 function.
Project Description:
We propose to test whether a Nurr1-RXR agonist can interfere with alterations in gene expression caused by 6-OHDA injection or alpha-synuclein overexpression. In addition the Nurr-1-dependance of these effects will be tested in Nurr1 conditional knockout models.
Finally, we will determine if a Nurr1-RXR agonist can provide neuroprotection in the newly established AAV-alpha-synuclein model of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Evaluating the effect of a Nurr1-RXR agonist in well-established and complementary models of PD is an important step to determine the therapeutic potential of such compounds.
Anticipated Outcome:
If successful results are obtained in the AAV-alpha-synuclein model, this would give a strong proof-of-concept for testing Nurr1-RXR agonists in patients with PD and for further development of similar compounds.
Final Outcome
Nurr1 is a survival factor in dopamine neurons. Recent work has identified Nurr1 as a possible new therapeutic target for neuroprotection and disease intervention in Parkinson´s disease and several drug companies are currently developing drugs that can act as activators of Nurr1. The first of this class of compounds that came to our attention was Bexarotene which is already in clinical use for treatment of certain cancers. Based on promising data obtained by other investigators we decided to explore the potential of Bexarotene, given daily by the oral route, to protect midbrain dopamine neurons in two different models of Parkinson´s disease, i.e. the 6-hydroxydopamine toxin model and the alpha-synuclein overexpression model. The results were overall negative: Bexarotene at the recommended doses did not afford any measurable neuroprotection in either model, and in a separate experiment we could not observe any clear effect of the drug on cell survival signaling. The results suggest that Bexarotene in the doses used here does not induce a sufficient level of Nurr1 activation to afford neuroprotection. Nevertheless the search for more potent Nurr1 activators seems highly warranted.