RGS10 Mediates Changes in Gut Permeability and Inflammation After an Intestinal Inflammatory Challenge

Abstract

Parkinson's disease (PD) pathology is marked by degeneration of dopamine neurons and the accumulation of the protein alpha‐synuclein in Lewy bodies in the Substantia Nigra pars Compacta (SNPC). A lesser known aspect of PD pathology is chronic intestinal inflammation which may promote the progression of the disease by dysregulating alpha‐synuclein in the gut. Regulator of G‐protein signaling 10 (RGS10) is a GTPase‐activating protein that is expressed in intestinal immune cells and acts as an anti‐inflammatory regulator by inhibiting NFkB. Previous studies have also shown that RGS10 knock‐out mice developed dopamine neuron loss in the SNPC after systemic lipopolysaccharide exposure. We have also found that mice deficient in RGS10 have higher levels of NFkB in the intestine, significantly shorter intestine lengths, increased fecal water content, and changes in tight junction protein expression. We predicted that reductions in RGS10 expression would increase inflammation and permeability in the intestine to a greater extent in the context of a chemical inflammatory challenge, modeling, perhaps, the contribution of pronounced intestinal inflammation to Parkinsonian neuropathology. To evaluate this, we subjected RGS10 knockout, heterozygous, and wild‐type mice to a dextran sodium sulfate (DSS) colitis model. We took baseline measurements of weight as well as peripheral blood immune cell populations by flow cytometry. For a total of 14 days, mice were monitored for weight loss and bloody stool. At the end of the experiment, a FITC‐dextran gut permeability assay was performed. The mice were then sacrificed, and small intestine and colon length were measured, along with cecum weight. We collected blood, brain, and gut tissue for flow cytometry, qPCR, and Western blots. We found that RGS10 knockout mice have significant changes in immune cell population. We will compare the effect of RGS10 deficiency on levels of intestinal inflammation at baseline and after DSS. Our work will demonstrate that RGS10 deficiency leads to changes in intestinal structure and immunity, which can increase the risk for Parkinsonian‐like pathology in knockout mice.Support or Funding InformationAcknowledgments: This work was supported by NSF Graduate Research Fellowship DGE‐1444932 and the American Physiological Society's Undergraduate Summer Research Fellowship. A special thank you to the Tansey Lab and the Emory University Department of Physiology.