Microglia are brain-resident macrophages responsible for immune surveillance. These cells become activated in response to injury, infection, environmental toxins, and other stimuli, thereby critically influencing neuronal survival and brain function. A wealth of clinical and experimental data implicate chronic microglia activation and overproduction of inflammatory mediators in the pathogenesis of Parkinson's disease (PD), the pathological hallmark of which is loss of ventral midbrain dopaminergic (DA) neurons that control output from motor cortex. However, the key molecular regulators of neuroinflammatory responses in the ventral midbrain have yet to be identified. The goals of this proposal are to investigate the role of Regulator of G-protein Signaling (RGS)-10, a GTPase Accelerating Protein (GAP) enriched in microglia, in neuroinflammatory responses that influence the vulnerability of nigral DA neurons to inflammation-induced degeneration.
In Specific Aim 1 we will investigate the role of RGS10 in microglia activation and impact on survival of dopaminergic neurons using cell-based and rodent models.
In Specific Aim 2, we will define the molecular mechanism and signaling pathways involved in RGS10-dependent regulation of activation responses and gene expression in microglia using cell-based models.
In Specific Aim 3 we will investigate the extent to which aging and neurodegeneration affect mouse and human RGS10 expression in microglia and peripheral macrophages. Completion of the proposed experiments will provide new information regarding the function of RGS10 in microglia and in neuroinflammatory responses in the ventral midbrain and may reveal novel targets for development of new therapies to prevent or treat PD, the second most common neurodegenerative disorder in the U.S.

Public Health Relevance

Parkinson's disease (PD) is the second most common neurodegenerative disease in the U.S. affecting 1-2% of individuals over age 60. Inflammatory processes have been strongly implicated in the pathogenesis of PD. The proposed studies will determine the role of RGS10 in microglia activation responses in protecting dopaminergic neurons against inflammation-induced degeneration. Completion of the proposed experiments may reveal new targets for therapies to prevent or delay development of PD in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072467-04
Application #
8521404
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Sieber, Beth-Anne
Project Start
2010-09-15
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$320,652
Indirect Cost
$113,780
Name
Emory University
Department
Physiology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lee, Jae-Kyung; Kannarkat, George T; Chung, Jaegwon et al. (2016) RGS10 deficiency ameliorates the severity of disease in experimental autoimmune encephalomyelitis. J Neuroinflammation 13:24
Joers, Valerie; Tansey, Malú G; Mulas, Giovanna et al. (2016) Microglial phenotypes in Parkinson's disease and animal models of the disease. Prog Neurobiol :
Kannarkat, G T; Cook, D A; Lee, J-K et al. (2015) Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson's Disease: An Observational and Case-Control Study. NPJ Parkinsons Dis 1:
Kannarkat, George T; Lee, Jae-Kyung; Ramsey, Chenere P et al. (2015) Age-related changes in regulator of G-protein signaling (RGS)-10 expression in peripheral and central immune cells may influence the risk for age-related degeneration. Neurobiol Aging 36:1982-93
Ramsey, Chenere P; Tansey, Malú G (2014) A survey from 2012 of evidence for the role of neuroinflammation in neurotoxin animal models of Parkinson's disease and potential molecular targets. Exp Neurol 256:126-32
Harms, Ashley S; Tansey, Malú G (2013) Isolation of murine postnatal brain microglia for phenotypic characterization using magnetic cell separation technology. Methods Mol Biol 1041:33-9
Lee, Jae-Kyung; Tansey, Malú G (2013) Microglia isolation from adult mouse brain. Methods Mol Biol 1041:17-23
Kannarkat, George T; Boss, Jeremy M; Tansey, Malú G (2013) The role of innate and adaptive immunity in Parkinson's disease. J Parkinsons Dis 3:493-514
Lee, Jae-Kyung; Chung, Jaegwon; Kannarkat, George T et al. (2013) Critical role of regulator G-protein signaling 10 (RGS10) in modulating macrophage M1/M2 activation. PLoS One 8:e81785
Lee, Jae-Kyung; Chung, Jaegwon; Druey, Kirk M et al. (2012) RGS10 exerts a neuroprotective role through the PKA/c-AMP response-element (CREB) pathway in dopaminergic neuron-like cells. J Neurochem 122:333-43

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