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- W2945693790 abstract "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 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 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-Gi/o signaling in SNc dopamine neurons, protecting against PD neurodegeneration and α-synuclein accumulation." @default.
- W2945693790 created "2019-05-29" @default.
- W2945693790 creator A5011137749 @default.
- W2945693790 creator A5032551597 @default.
- W2945693790 creator A5035719283 @default.
- W2945693790 creator A5058526198 @default.
- W2945693790 creator A5066901683 @default.
- W2945693790 creator A5070959796 @default.
- W2945693790 creator A5080153002 @default.
- W2945693790 creator A5082128655 @default.
- W2945693790 date "2019-07-11" @default.
- W2945693790 modified "2023-10-18" @default.
- W2945693790 title "Age-dependent nigral dopaminergic neurodegeneration and α-synuclein accumulation in RGS6-deficient mice" @default.
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