Journal article
RGS Proteins as Critical Regulators of Motor Function and Their Implications in Parkinson's Disease
Molecular pharmacology, Vol.98(6), pp.730-738
12/2020
DOI: 10.1124/mol.119.118836
PMCID: PMC7662528
PMID: 32015009
Abstract
Parkinson disease (PD) is a devastating, largely nonfamilial, age-related disorder caused by the progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Release of DA from these neurons into the dorsal striatum is crucial for regulating movement and their loss causes PD. Unfortunately, the mechanisms underlying SNc neurodegeneration remain unclear, and currently there is no cure for PD, only symptomatic treatments. Recently, several regulator of G protein signaling (RGS) proteins have emerged as critical modulators of PD pathogenesis and/or motor dysfunction and dyskinesia: RGSs 4, 6, 9, and 10. Striatal RGS4 has been shown to exacerbate motor symptoms of DA loss by suppressing M
-autoreceptor-G
signaling in striatal cholinergic interneurons. RGS6 and RGS9 are key regulators of D
R-G
signaling in SNc DA neurons and striatal medium spiny neurons, respectively. RGS6, expressed in human and mouse SNc DA neurons, suppresses characteristic PD hallmarks in aged mice, including SNc DA neuron loss, motor deficits, and
-synuclein accumulation. After DA depletion, RGS9 (through its inhibition of medium spiny neuron D
R signaling) suppresses motor dysfunction induced by L-DOPA or D
R-selective agonists. RGS10 is highly expressed in microglia, the brain's resident immune cells. Within the SNc, RGS10 may promote DA neuron survival through the upregulation of prosurvival genes and inhibition of microglial inflammatory factor expression. Thus, RGSs 4, 6, 9, and 10 are critical modulators of cell signaling pathways that promote SNc DA neuron survival and/or proper motor control. Accordingly, these RGS proteins represent novel therapeutic targets for the treatment of PD pathology. SIGNIFICANCE STATEMENT: Parkinson disease (PD), the most common movement disorder, is a progressive neurodegenerative disease characterized by substantia nigra pars compacta (SNc) dopamine (DA) neuron loss and subsequent motor deficits. Current PD therapies only target disease motor symptomology and are fraught with side effects. Therefore, researchers have begun to explore alternative therapeutic options. Regulator of G protein signaling (RGS) proteins, whether primarily expressed in SNc DA neurons (RGS6), striatal neurons (RGSs 4 and 9), or microglia (RGS10), modulate key signaling pathways important for SNc DA neuron survival and/or proper motor control. As such, RGS proteins represent novel therapeutic targets in PD.
Details
- Title: Subtitle
- RGS Proteins as Critical Regulators of Motor Function and Their Implications in Parkinson's Disease
- Creators
- Katelin E Ahlers-Dannen - Department of Neuroscience and Pharmacology (K.E.A.-D., M.M.S., R.A.F.), Iowa Neuroscience Institute (R.A.F.), and Interdisciplinary Graduate Program in Molecular Medicine (M.M.S., R.A.F.), University of Iowa Carver College of Medicine, Iowa City, IowaMackenzie M Spicer - Department of Neuroscience and Pharmacology (K.E.A.-D., M.M.S., R.A.F.), Iowa Neuroscience Institute (R.A.F.), and Interdisciplinary Graduate Program in Molecular Medicine (M.M.S., R.A.F.), University of Iowa Carver College of Medicine, Iowa City, IowaRory A Fisher - Department of Neuroscience and Pharmacology (K.E.A.-D., M.M.S., R.A.F.), Iowa Neuroscience Institute (R.A.F.), and Interdisciplinary Graduate Program in Molecular Medicine (M.M.S., R.A.F.), University of Iowa Carver College of Medicine, Iowa City, Iowa rory-fisher@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Molecular pharmacology, Vol.98(6), pp.730-738
- Publisher
- United States
- DOI
- 10.1124/mol.119.118836
- PMID
- 32015009
- PMCID
- PMC7662528
- ISSN
- 0026-895X
- eISSN
- 1521-0111
- Grant note
- R01 AA025919 / NIAAA NIH HHS T32 GM067795 / NIGMS NIH HHS
- Language
- English
- Date published
- 12/2020
- Academic Unit
- Neurology; Psychiatry; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984070508502771
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