Age-dependent nigral dopaminergic neurodegeneration and α-synuclein accumulation in RGS6-deficient mice.

1. JCI Insight. 2019 May 23;5(13):e126769. doi: 10.1172/jci.insight.126769. Age-dependent nigral dopaminergic neurodegeneration and α-synuclein accumulation in RGS6-deficient mice. Luo Z(1), Ahlers-Dannen KE(1), Spicer MM(1)(2), Yang J(1), Alberico S(3), Stevens HE(4), Narayanan NS(5), Fisher RA(1). Author information: (1)Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. (2)Interdisciplinary Graduate Program of Molecular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. (3)Department of Neurology, New York University, New York, New York, USA. (4)Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. (5)Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. Parkinson's is primarily a non-familial, age-related disorder caused by α-synuclein accumulation and the progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc). G protein-coupled receptor (GPCR)-cAMP signaling has been linked to a reduction in human Parkinson's incidence and α-synuclein expression. Neuronal cAMP levels are controlled by GPCRs coupled to Gs or Gi/o, which increase or decrease cAMP, respectively. Regulator of G protein signaling 6 (RGS6) powerfully inhibits Gi/o signaling. Therefore, we hypothesized that RGS6 suppresses D2 autoreceptor- Gi/o signaling in SNc dopamine neurons promoting neuronal survival and reducing α-synuclein expression. Here we provide novel evidence that RGS6 critically suppresses late-age-onset SNc dopamine neuron loss and α-synuclein accumulation. RGS6 is restrictively expressed in human SNc dopamine neurons and, despite their loss in Parkinson's, all surviving neurons express RGS6. RGS6-/- mice exhibit hyperactive D2 autoreceptors with reduced cAMP signaling in SNc dopamine neurons. Importantly, RGS6-/- mice recapitulate key sporadic Parkinson's hallmarks, including: SNc dopamine neuron loss, reduced nigrostriatal dopamine, motor deficits, and α-synuclein accumulation. To our knowledge, Rgs6 is the only gene whose loss phenocopies these features of human Parkinson's. Therefore, RGS6 is a key regulator of D2R-Gi/o signaling in SNc dopamine neurons, protecting against Parkinson's neurodegeneration and α-synuclein accumulation. DOI: 10.1172/jci.insight.126769 PMCID: PMC6629243 PMID: 31120439 [Indexed for MEDLINE] Conflict of interest statement: Conflict of interest: The authors have declared that no conflict of interest exists.