Dual Nurr1/RXR agonism of valerenic acid and synthetic mimetics enables dimer-selective Nurr1 modulation.

Nuclear receptor related 1 (Nurr1) is a neuroprotective transcription factor emerging as promising target in Parkinson's disease and multiple sclerosis. It can act in three oligomeric forms as monomer, homodimer and heterodimer on different DNA response elements. We hypothesized that dual Nurr1 and RXR activation might enable selective modulation of Nurr1 in its heterodimeric form. A search for dual ligands revealed valerenic acid and a synthetic mimetic as Nurr1 and RXR activators. Biochemical and cellular characterization demonstrated that dual agonism destabilized the Nurr1 homodimer but left the heterodimer intact which translated into selective activation of the heterodimer response element in cells. In neuronal cells, a dual Nurr1/RXR agonist enhanced expression of only a subset of Nurr1 agonist induced genes providing initial proof-of-concept for the dimer-directed selective Nurr1 modulation approach.