Abstract. Regulator of G-protein signaling (RGS) proteins were originally identified as negative regulators of G-protein-coupled receptor (GPCR) signaling via their GTPase-accelerating protein (GAP) activity. All RGS proteins contain evolutionarily conserved RGS domain; however, they differ in their size and regulatory domains. RGS1 and RGS10 are smaller than other RGS proteins, and their functions involve various inflammatory responses including autoimmune responses in both the periphery and the central nervous system (CNS). Neuroinflammation is the chronic inflammatory response in the CNS. Acute inflammatory response in the CNS is believed to be beneficial by involving the neuroprotective actions of immune cells in the brain, particularly microglia, to limit tissue damage and to aid in neuronal repair. However, chronically elevated levels of cytokines serve to maintain activation of abundant numbers of immune cells potentiating prolonged inflammatory responses and creating an environment of oxidative stress, which further hastens oxidative damage of neurons. In this review, we describe the implications and features of RGS proteins (specifically RGS1 and RGS10) in neuroinflammation and neurodegenerative diseases. We will discuss the experimental and epidemiological evidence on the benefits of anti-inflammatory interventions by targeting RGS1 and/or RGS10 protein function or expression in order to delay or attenuate the progression of neurodegeneration, particularly in multiple sclerosis (MS) and Parkinson's disease (PD).
Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [160, 377, 411, 415, 416, 512, 519, 312, 6].
Bisphenol A (BPA) and Diethylhexyl Phthalate (DEHP) are common environmental endocrine disrupting chemicals (EDCs) that exert a range of potential adverse health effects. EDC exposure can occur in utero and during early postnatal life, when organ systems are differentiating resulting in a number of disorders in adulthood. The aim of this study was to evaluate the immunotoxic effect of prenatal exposure to individual and combinations of BPA and DEHP on male and female rat thymus. From gestational day 6 till 21, Sprague Dawley dams were orally administered either saline (control; n=7), BPA (5μg/Kg BW; n=7), DEHP (7.5mg/Kg BW; n=7), or a mixture of BPA and DEHP (B+D; n=7). Male and female offspring were sacrificed at 16 weeks of age. Thymus and spleen were dissected, weighed, and stored for further processing. Our data showed that spleen weight to body weight (BW) ratio of EDC treated offspring were comparable to those from age‐matched control rats. However, male offspring (but not females) that were prenatally exposed to BPA alone exhibited a 40% decrease (p<0.01) and those exposed to DEHP alone had a 27% reduction in thymus/BW ratio (p<0.05). To understand if prenatal EDC exposure was promoting early thymus involution through apoptosis, we performed Terminal deoxynucleotidyl transferase‐dUTP nick end labeling (TUNEL) staining of nicked DNA on thymic sections. There was significant apoptosis in the thymic cortex in both male and female offspring that were prenatally exposed to individual EDCs. Apoptosis was hardly detected in the medullary region. Apoptosis in the B+D group was markedly reduced compared to individual EDC exposures. These results suggest that prenatal exposure to even low BPA and moderate DEHP levels can promote apoptosis in the thymus. This could possibly affect immune functions in adulthood. Interestingly, exposure to a mixture of these EDCs did not produce any significant change in apoptosis in the thymus.Support or Funding InformationSupported by UGA Research Foundation and start‐up funds.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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