Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor a (RXRa) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRa-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner.;Furthermore, Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits and played neuroprotective and anti-inflammatory roles in MPTP-induced PD mice by down-regulating CCL2 in vivo.