Modulation of GPRC6a Signaling to Mitigate Tauopathies

General Abstract Tauopathies are age-associated neurodegenerative diseases. Evidence shows altered arginine metabolism and dysregulation of the polyamine system in Alzheimer’s disease. Arginine metabolism represents a critical branch- point affecting multiple biological processes and seems to show a considerable affects upon tau biology. We identified that overexpressing other arginine metabolizing enzymes such as arginase 1 reduces tau pathology in mouse models of tauopathy. Tau overexpressing cell models show similar effects with parallel arginase 1 manipulations. We identified several mechanisms by which arginine metabolism governs tau fate, one of which includes activation of autophagy possibly through possible amino acid sensing of L-arginine. GPRC6a is a G- protein coupled receptor that binds L-α amino acids including L-arginine. We hypothesize that decreased signaling of GPRC6a or allosteric antagonism to GPRC6a activates autophagy and tau clearance. Herein, we will identify the mechanism by which GPRC6a modifies tau neuropathology by three methods including: genetic knockout of GPRC6a, genetic knock down by gene therapy, and pharmacological antagonism. We will determine if GPRC6a knockout mice show reduced tau accumulation in the brains of mice. We will determine if adeno associated viral knockdown of GPRC6a reduces the tau pathology and improve behavioral outcomes. We will identify if selective GPRC6a allosteric antagonists increase tau degradation. Success in this application would provide a new receptor target that activates autophagy through amino acid sensing to mitigate the tau phenotype. Our goal from the studies conducted comprises of identifying viable targets that could be drugable, or induced to provide maximum benefit with respect to tauopathies and Alzheimer’s disease, but minimal changes in a host of other body systems. Scope of work: SPECIFC AIM 1: To determine if GPRC6a knockout mice show reduced accumulation of tau pathology. Rationale Aim1: We will test the hypothesis that GPRC6a deletion promotes tau clearance mediated by adeno associated viral (rAAV) tau overexpression compared to wild-type littermates SPECIFC AIM 2: To determine if rAAV-mediated shRNA knockdown of GPRC6a reduces the tau phenotype. Rationale Aim2: We will test the hypothesis that viral mediated shRNA knockdown of GPRC6a induces autophagy and mitigates tau neuropathology in rTg4510 transgenic mice. SPECIFC AIM 3: To identify if selective GPRC6a allosteric antagonists increase tau degradation and clearance. We will test the hypothesis that novel and selective GPRC6a allosteric antagonists increase autophagy and tau clearance in vitro.