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The Journal of Neuroscience, August 20, 2008, 28(34):8517-8528; doi:10.1523/JNEUROSCI.1806-08.2008

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Neurobiology of Disease
Regulator of G-Protein Signaling 10 Promotes Dopaminergic Neuron Survival via Regulation of the Microglial Inflammatory Response

Jae-Kyung Lee,¹ Melissa K. McCoy,¹ Ashley S. Harms,¹ Kelly A. Ruhn,¹ Stephen J. Gold,² and Malú G. Tansey¹

Departments of ¹Physiology and ²Psychiatry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9040

Correspondence should be addressed to Dr. Malú G. Tansey, Assistant Professor of Physiology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9040. Email: malu.tansey{at}utsouthwestern.edu

Epidemiological studies suggest that chronic use of nonsteroidal anti-inflammatory drugs lowers the incidence of Parkinson's disease (PD) in humans and implicate neuroinflammatory processes in the death of dopamine (DA) neurons. Here, we demonstrate that regulator of G-protein signaling 10 (RGS10), a microglia-enriched GAP (GTPase accelerating protein) for G subunits, is an important regulator of microglia activation. Flow-cytometric and immunohistochemical analyses indicated that RGS10-deficient mice displayed increased microglial burden in the CNS, and exposure to chronic systemic inflammation induced nigral DA neuron loss measured by unbiased stereology. Primary microglia isolated from brains of RGS10-deficient mice displayed dysregulated inflammation-related gene expression profiles under basal and stimulated conditions in vitro compared with that of primary microglia isolated from wild-type littermates. Similarly, knockdown of RGS10 in the BV2 microglia cell line resulted in dysregulated inflammation-related gene expression, overproduction of tumor necrosis factor (TNF), and enhanced neurotoxic effects of BV2 microglia on the MN9D dopaminergic cell line that could be blocked by addition of the TNF decoy receptor etanercept. Importantly, ablation of RGS10 in MN9D dopaminergic cells further enhanced their vulnerability to microglial-derived death-inducing inflammatory mediators, suggesting a role for RGS10 in modulating the sensitivity of dopaminergic neurons against inflammation-mediated cell death. Together, our findings indicate that RGS10 limits microglial-derived TNF secretion and regulates the functional outcome of inflammatory stimuli in the ventral midbrain. RGS10 emerges as a novel drug target for prevention of nigrostriatal pathway degeneration, the neuropathological hallmark of PD.

Key words: RGS10; microglia; neuroinflammation; tumor necrosis factor; dopaminergic neurodegeneration; Parkinson's disease

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Received Jan. 25, 2008; revised June 17, 2008; accepted July 11, 2008.

Correspondence should be addressed to Dr. Malú G. Tansey, Assistant Professor of Physiology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9040. Email: malu.tansey{at}utsouthwestern.edu

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