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Regulator of G-protein signaling 10 promotes dopaminergic neuron survival via regulation of the microglial inflammatory response.

ABSTRACT: 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 Galpha 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.

SUBMITTER: Lee JK

PROVIDER: S-EPMC2739568 | biostudies-other | 2008 Aug

REPOSITORIES: biostudies-other

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Regulator of G-protein signaling 10 promotes dopaminergic neuron survival via regulation of the microglial inflammatory response.

Lee Jae-Kyung JK McCoy Melissa K MK Harms Ashley S AS Ruhn Kelly A KA Gold Stephen J SJ Tansey Malú G MG

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080801 34

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 Galpha subunits, is an important regulator of microglia activation. Flow-cytometric and immunohistochemical analyses indicated that RGS10-def ...[more]

PMID: 18716210

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Project description:In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a(+/-) mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rates in the Dyrk1a haploinsufficient model and in a model (the mBACtgDyrk1a mouse) that carries three copies of Dyrk1a. We also show that the number of mDA cells diminishes in postnatal Dyrk1a(+/-) mice and increases in mBACtgDyrk1a mice due to an abnormal activity of the mitochondrial caspase9 (Casp9)-dependent apoptotic pathway during the main wave of PCD that affects these neurons. In addition, we show that the cell death induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), a toxin that activates Casp9-dependent apoptosis in mDA neurons, is attenuated in adult mBACtgDyrk1a mice, leading to an increased survival of SN DA neurons 21 days after MPTP intoxication. Finally, we present data indicating that Dyrk1a phosphorylation of Casp9 at the Thr125 residue is the mechanism by which this kinase hinders both physiological and pathological PCD in mDA neurons. These data provide new insight into the mechanisms that control cell death in brain DA neurons and they show that deregulation of developmental apoptosis may contribute to the phenotype of patients with imbalanced DYRK1A gene dosage.

Dataset Information

Regulator of G-protein signaling 10 promotes dopaminergic neuron survival via regulation of the microglial inflammatory response.

Publications

Regulator of G-protein signaling 10 promotes dopaminergic neuron survival via regulation of the microglial inflammatory response.

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