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

Zili Luo, Katelin E. Ahlers-Dannen, Mackenzie M. Spicer, Jianqi Yang, Stephanie Alberico, Hanna E. Stevens, Nandakumar S. Narayanan, Rory A. Fisher

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Article numbere126769
JournalJCI Insight
Volume4
Issue number13
DOIs
StatePublished - Jul 11 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright: © 2019 American Society for Clinical Investigation

Fingerprint

Dive into the research topics of 'Age-dependent nigral dopaminergic neurodegeneration and α-synuclein accumulation in RGS6-deficient mice'. Together they form a unique fingerprint.

Cite this