Nutrient sensing receptor GPRC6A regulates mTORC1 signaling and Tau biology

Tauopathies, including Alzheimer's disease (AD), comprise microtubule-associated protein tau aggregates that cause neuronal cell death and clinical cognitive decline. Reducing overall tau abundance remains a central strategy for therapeutics; however, no disease-modifying treatment exists to date. One principal pathway for balancing cellular proteostasis includes the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Recently, arginine emerged as one of the primary amino acids to activate mTORC1 through several intracellular arginine sensors and an extracellular arginine receptor, namely the G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A). Human AD brains were previously reported with elevated mTORC1 signaling; however, it is unclear whether arginine sensing and signaling to mTORC1 plays a role in tauopathies. Herein, we examined arginine sensing associated with mTORC1 signaling in the human AD and animal models of tauopathy. We found that human AD brains maintained elevated levels of arginine sensors with potential uncoupling of arginine sensing pathways. Furthermore, we observed increased GPRC6A and arginine in the brain, accompanied by increased mTORC1 signaling and decreased autophagy in a mouse model of tauopathy (Tau PS19). We also discovered that both supplementing arginine and overexpressing GPRC6A in cell culture models could independently activate mTORC1 and promote tau accumulation. In addition, we found that suppressing GPRC6A signaling by either genetic reduction or pharmacological antagonism reduced tau accumulation, phosphorylation, and oligomerization. Overall, these findings uncover the crucial role of arginine sensing pathways in deregulating mTORC1 signaling in tauopathies and identify GPRC6A as a promising target for future therapeutics in tauopathies and other proteinopathies. SIGNIFICANCE STATEMENT: Tauopathies, including Alzheimer's disease (AD), accumulate pathogenic tau protein inclusions that potentially contribute to the hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling and eventually cause neuronal cell death. Here, we presented novel findings that AD and animal models of tauopathy maintained increased expression of arginine sensors and uncoupling of arginine sensing associated with mTORC1 signaling. We investigated the role of a putative extracellular arginine and basic L-amino acid sensing G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A) in activating mTORC1 and accelerating pathogenic tau phenotypes in several cell models. Additionally, we showed that genetic repression or antagonism of GPRC6A signaling provides a novel therapeutic target for tauopathies and other proteinopathies.