Age-dependent nigral dopaminergic neurodegeneration and α-synuclein accumulation in RGS6-deficient mice
| Autor: | Zili Luo, Stephanie Alberico, Nandakumar S. Narayanan, Mackenzie M. Spicer, Rory A. Fisher, Katelin E. Ahlers-Dannen, Hanna E. Stevens, Jianqi Yang |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Parkinson's disease Quinpirole Dopamine Substantia nigra Biology Synaptic Transmission 03 medical and health sciences Mice 0302 clinical medicine Regulator of G protein signaling medicine Animals Humans Age of Onset Pars Compacta Mice Knockout Pars compacta Receptors Dopamine D2 Dopaminergic Neurons Dopaminergic Neurodegeneration Age Factors Parkinson Disease General Medicine medicine.disease nervous system diseases Cell biology 030104 developmental biology nervous system 030220 oncology & carcinogenesis Dopamine Agonists Autoreceptor alpha-Synuclein Locomotion RGS Proteins medicine.drug Research Article |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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