TY - JOUR T1 - RGS proteins as critical regulators of motor function and their implications in Parkinson's disease JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.119.118836 SP - mol.119.118836 AU - Katelin E Ahlers-Dannen AU - Mackenzie M. Spicer AU - Rory A. Fisher Y1 - 2020/01/01 UR - http://molpharm.aspetjournals.org/content/early/2020/02/03/mol.119.118836.abstract N2 - Parkinson's disease (PD) is a devastating, largely non-familial age-related disorder caused by the progressive loss of dopamine (DA) neurons in the SNc. Release of DA from these neurons into the dorsal striatum is crucial for regulating movement and their loss causes PD. Unfortunately, the mechanisms underlying SNc neurodegeneration remain unclear, and currently there is no cure for PD, only symptomatic treatments. Recently, several regulator of G protein signaling (RGS) proteins have emerged as critical modulators of PD pathogenesis and/or motor dysfunction and dyskinesia: RGSs 4, 6, 9 and 10. Striatal RGS4 has been shown to exacerbate motor symptoms of DA loss by suppressing M4 autoreceptor-Gαi/o signaling in striatal cholinergic interneurons. RGS6 and RGS9 are key regulators of D2R-Gαi/o signaling in SNc DA neurons and striatal medium spiny neurons (MSNs), respectively. RGS6, expressed in human and mouse SNc DA neurons, suppresses characteristic PD hallmarks in aged mice, including SNc DA neuron loss, motor deficits, and α-synuclein accumulation. Following DA depletion, RGS9, through its inhibition of MSN D2R signaling, suppresses motor dysfunction induced by L-DOPA or D2R-selective agonists. RGS10 is highly expressed in microglia, the brain's resident immune cells. Within the SNc, RGS10 may promote DA neuron survival through the upregulation of pro-survival genes and inhibition of microglial inflammatory factor expression. Thus, RGSs 4, 6, 9, and 10 are critical modulators of cell signaling pathways that promote SNc DA neuron survival and/or proper motor control. Accordingly, these RGS proteins represent novel therapeutic targets for the treatment of PD pathology.SIGNIFICANCE STATEMENT Parkinson’s (PD), the most common movement disorder, is a progressive neurodegenerative disease characterized by SNc dopamine neuron loss and subsequent motor deficits. Current PD therapies only target disease motor symptomology and are fraught with side effects. Therefore, researchers have begun to explore alternative therapeutic options. Regulator of G protein signaling (RGS) proteins, whether primarily expressed in SNc DA neurons (RGS6), striatal neurons (RGSs 4 and 9), or microglia (RGS10), modulate key signaling pathways important for SNc dopamine neuron survival and/or proper motor control. As such, RGS proteins represent novel therapeutic targets in PD. ER -