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

JCI Insight. 2019 May 23;5(13):e126769. doi: 10.1172/jci.insight.126769.


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.

Keywords: G-protein coupled receptors; G-proteins; Neuroscience; Parkinson's disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Age of Onset
  • Animals
  • Dopamine / metabolism
  • Dopamine Agonists / pharmacology
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • Humans
  • Locomotion
  • Mice
  • Mice, Knockout
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Parkinson Disease / physiopathology
  • Pars Compacta / cytology
  • Pars Compacta / metabolism*
  • Pars Compacta / pathology
  • Quinpirole / pharmacology
  • RGS Proteins / genetics*
  • RGS Proteins / metabolism*
  • Receptors, Dopamine D2 / metabolism*
  • Synaptic Transmission
  • alpha-Synuclein / metabolism*


  • DRD2 protein, mouse
  • Dopamine Agonists
  • RGS Proteins
  • RGS6 protein, human
  • Receptors, Dopamine D2
  • Rgs6 protein, mouse
  • Snca protein, mouse
  • alpha-Synuclein
  • Quinpirole
  • Dopamine