Regulator of G-protein Signaling (RGS)1 and RGS10 Proteins as Potential Drug Targets for Neuroinflammatory and Neurodegenerative Diseases

Abstract

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).

Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy

“…Recent studies demonstrated also that SMC4 is associated with tumor progression and invasion and the expression of SMC4 is positively correlated with HIF-1a 30 . RGS1 protein is the most abundant RGS protein in the microglia and is a key gene of the immunomodulatory response to neuroinflammation as well as a key target of different immunological and neurodegenerative diseases such as multiple sclerosis, inflammatory bowel and Parkinson's disease 33,34 . Recent evidence suggests that RGS1 protein is involved in the hypoxia-dependent inflammatory response 35,36 , through activation of the AKT signalling pathway, which is switched-on after chronic moderate hypoxia.…”

Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes

“…RGS1 is expressed in lymphocytes, dendritic cells, monocytes (Bansal, Druey, & Xie, 2007), and microglia (Atwood, Lopez, Wager‐Miller, Mackie, & Straiker, 2011). It has been reported that B lymphocytes in germinal centers (GC) within follicles of lymphoid organs express especially high levels of RGS1 (Moratz et al, 2000), which codes for the regulator of G‐protein signaling 1, a protein located on the cytosolic side of the plasma membrane that acts as a negative regulator of G‐protein‐coupled receptors signaling (Lee & Bou Dagher, 2016). The fact that all chemokine receptors are coupled to heterotrimeric G‐proteins (Ansel & Cyster, 2001) promoted the investigation of the role of RGS1 in the response to chemokine stimulation and led to uncover that B cells in RGS1 −/− mice respond extremely to the chemokines CXCL12 (CXCR4 ligand) and CXCL13 (CXCR5 ligand; Moratz, Hayman, Gu, & Kehrl, 2004).…”

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

“…With nearly every new function revealed, the role of a small molecule that would be useful as a drug or probe molecule for further investigation can be inferred. There are a number of recent publications on RGS proteins in cancer (17), inflammation (18), cardiovascular processes (19 -21), neuroinflammation (22), and even pregnancy (23, 24) that describe the diverse role RGS proteins play in these processes. In this review we will present examples that help reinforce the rationale behind the search for RGS inhibitors, in particular, those focused on neurological disorders and cancer.…”

“…SNPs (rs2332700 and rs4899412) in RGS6 provide genetic evidence for the association of RGS6 with schizophrenia and Alzheimer's disease, respectively (56,57). Additional SNPs found in other RGS proteins suggest a genetic predisposition for certain central nervous system disease states (22,58), such as a SNP found in RGS1 (rs10492972) that is significantly associated with the diagnosis of multiple sclerosis (22,59).…”