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

Parkinson’s disease (PD) is primarily a nonfamilial, age-related disorder caused by α-synuclein accumulation and the progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc). GPCR-cAMP signaling has been linked to a reduction in human PD incidence and α-synuclein expression. Neuronal cAMP levels are controlled by GPCRs coupled to G_s or G_i/o, which increase or decrease cAMP, respectively. Regulator of G protein signaling 6 (RGS6) powerfully inhibits G_i/o signaling. Therefore, we hypothesized that RGS6 suppresses D₂ autoreceptor-G_i/o signaling in SNc dopamine neurons promoting neuronal survival and reducing α-synuclein expression. Here, we provide potentially 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 PD, 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 PD 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 PD. Therefore, RGS6 is a key regulator of D₂R-G_i/o signaling in SNc dopamine neurons, protecting against PD neurodegeneration and α-synuclein accumulation.