Journal article
Age-dependent nigral dopaminergic neurodegeneration and α-synuclein accumulation in RGS6-deficient mice
JCI insight, Vol.4(13), e126769
07/11/2019
DOI: 10.1172/jci.insight.126769
PMCID: PMC6629243
PMID: 31120439
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 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 D
2
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 D
2
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 D
2
R-G
i/o
signaling in SNc dopamine neurons, protecting against PD neurodegeneration and α-synuclein accumulation.
Loss of G protein regulator RGS6 in mice recapitulates late-age onset dopamine neuron loss and α-synuclein accumulation in Parkinson’s neurodegeneration.
Details
- Title: Subtitle
- Age-dependent nigral dopaminergic neurodegeneration and α-synuclein accumulation in RGS6-deficient mice
- Creators
- Zili Luo - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAKatelin E Ahlers-Dannen - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAMackenzie M Spicer - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAJianqi Yang - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAStephanie Alberico - Department of Neurology, New York University, New York, New York, USAHanna E Stevens - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, USANandakumar S Narayanan - Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USARory A Fisher - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.4(13), e126769
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/jci.insight.126769
- PMID
- 31120439
- PMCID
- PMC6629243
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- CA161882 / ; AA025919 / ; T32GM067795 / University of Iowa NS09868 / ; T32HL007121 / ; 11551 / ;
- Language
- English
- Date published
- 07/11/2019
- Academic Unit
- Neurology; Psychiatry; Critical Care; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984070618702771
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