Regulator of G-protein Signaling (RGS)1 and RGS10 proteins as potential drug targets for neuroinflammatory and neurodegenerative diseases

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.

The AAPS Journal, Vol 18, No 3, May 2016 ( # 2016) DOI: 10.1208/s12248-016-9883-4 Review Article Theme: Heterotrimeric G Protein-based Drug Development: Beyond Simple Receptor Ligands Guest Editor: Shelley Hooks Regulator of G-protein Signaling (RGS)1 and RGS10 Proteins as Potential Drug Targets for Neuroinflammatory and Neurodegenerative Diseases Jae-Kyung Lee1,2 and Josephine Bou Dagher1 Received December 2015; accepted February 2016; published online 22 February 2016 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) KEY WORDS: G-protein-coupled receptor (GPCR); multiple sclerosis; neuroinflammation; Parkinson’s disease; regulator of G-protein signaling INTRODUCTION G-protein-coupled receptors (GPCRs) signal through heterotrimeric G-proteins that consist of an α subunit and a βγ heterodimer (1) Regulator of G-protein signaling (RGS) proteins play a role in turning off GPCR signaling All of the RGS proteins contain a conserved RGS domain that interacts with a Gαi, Gαq/11, or Gα12/13 subunit with variable selectivity, which accelerates the GTPase-activating activity of the Gα subunit (2–4) Since the mid-1990s, more than 30 functional RGS genes have been identified and subdivided into eight subfamilies that are expressed in eukaryotic organisms, from fungi to animals such as mice and humans (3, 5, 6) RGS proteins differ widely in their size and contain a variety of structural domains in addition to the RGS domain and motifs that regulate their activity and determine regulatory binding partners (3, 5; also reviewed in 6–9) Early Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, 501 D W Brooks Dr., Athens, Georgia 30602, USA To whom correspondence should be addressed (e-mail: jamlee@uga.edu) evidence suggested that RGS proteins acted primarily as negative regulators of G-protein signaling Today, it is well documented that these proteins act as tightly regulated modulators and multifunctional interactors of G-protein signaling (reviewed in 8) In addition, it has been recently appreciated that the non-RGS regions of RGS proteins can provide non-canonical functions distinct from the inactivation of Gα subunits or even from G-protein signaling entirely (reviewed in 9, 10) RGS proteins are highly conserved from yeast to mammals and are abundant in the retina, brain, heart, and immune organs (11; see review in 12) Tissue-specific patterns of RGS protein expression in the human peripheral tissues and brain were reported by Larminie and his group (13) They showed that the major RGS10 proteins in human lymphocytes are RGS1, RGS2, RGS10, RGS13, RGS14, RGS16, and RGS18 (13) The RGS proteins may acquire functional diversity in immune cells by a fine-tuned and dynamic regulation of the expression of multiple RGS proteins RGS protein profiling in human lymphocytes displays a similar expression profile to rodent lymphocytes except for RGS18 (14), suggesting that observations in rodent lymphocytes may be translated into what would be occurring in human lymphocytes In this review, we will discuss how RGS proteins, and more precisely RGS1 and RGS10, play 545 1550-7416/16/0300-0545/0 # 2016 American Association of Pharmaceutical Scientists RGS PROTEIN FAMILY AND MS MS is a chronic inflammatory disease of the central nervous system (CNS) associated with demyelination that is thought to have an underlying autoimmune etiology Currently in the USA, around 250,000–300,000 people have been diagnosed with MS and there are 200 new cases diagnosed every week Although there are varieties of immune-based therapeutic drugs available for the treatment of MS, it is difficult for clinicians to predict which drugs would work best for an individual patient due to a lack of mechanistic information of the disease (15) Also, major MS drugs target broad ranges of immune cells, which significantly affect leukocyte trafficking and function Therefore, it is important to identify biomarkers and/or cellular regulators specifically modulating function of autoimmune-reactive leukocytes Although the etiology of MS has not been identified, increasing evidence indicates that disease onset involves the combined influence of environmental factors and genetic susceptibility (16) GPCR signaling plays an important role in various aspects of MS pathogenesis including : antigen presentation, cytokine/chemokine production, and T-cell differentiation, proliferation, and invasion (see review in (17)) RGS family proteins that are important modulators of GPCR signaling pathways are recently implicated in the development of MS and other autoimmune diseases Multiple points of genetic evidences have shown the following: (1) single nucleotide polymorphisms (SNPs) of RGS1, RGS7, RGS9, and RGS14 are reported to be of high correlation with the diagnosis of MS, Crohn’s disease, and ulcerative colitis (18–22), and (2) the messenger RNA (mRNA) level of RGS10 and RGS1 is higher in peripheral blood mononuclear cells (PBMCs) from patients with MS according to the Gene Expression Omnibus (GEO) profile database (23, 24) However, the role of RGS proteins in the context of the onset or progression of autoimmune diseases is yet to be explored GC-RMA normalized signal intensity (Affimatrix array) important roles in inflammatory and neurodegenerative diseases and act as therapeutic potentials mainly in Parkinson’s disease (PD) and multiple sclerosis (MS) Lee and Bou Dagher GC-RMA normalized signal intensity (Affimatrix array) 546 RGS1 (NM_002922) 150 * 100 50 Control MS patient RGS1 (S59049) * 500 400 300 200 100 Control MS patient Fig RGS1 mRNA expression level is higher in peripheral blood mononuclear cells (PBMCs) of MS patients Microarray experiments identify genes and pathways involved in MS pathogenesis (data accessible at the NCBI GEO database, accession number GSE21942) PBMCs were isolated from the whole blood from 12 MS patients and 15 controls, and total RNA was extracted (22) GC-RMA refers Guanine Cytosine Robust Multi-Array Analysis *p