PT  - JOURNAL ARTICLE
AU  - Jae-Kyung Lee
AU  - Melissa K. McCoy
AU  - Ashley S. Harms
AU  - Kelly A. Ruhn
AU  - Stephen J. Gold
AU  - Malú G. Tansey
TI  - Regulator of G-Protein Signaling 10 Promotes Dopaminergic Neuron Survival via Regulation of the Microglial Inflammatory Response
AID  - 10.1523/JNEUROSCI.1806-08.2008
DP  - 2008 Aug 20
TA  - The Journal of Neuroscience
PG  - 8517--8528
VI  - 28
IP  - 34
4099  - http://www.jneurosci.org/content/28/34/8517.short
4100  - http://www.jneurosci.org/content/28/34/8517.full
SO  - J. Neurosci.2008 Aug 20; 28
AB  - 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 Gα 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.