Modulation of GPRC6A Signaling to Mitigate Tauopathies

Microtubule associated protein named tau, often becomes hyperphosphorylated and aggregates to form pathological neurofibrillary tangles in several age-associated neurodegenerative diseases known as tauopathies. Clinical phenotypes of tauopathies manifest as cognitive impairment, behavior disturbances and motor impairment. The aggregation of tau remains a central target for drug discovery, but currently no disease-modifying treatments exist. Our group has recently uncovered a unique interaction between L-arginine metabolism and tauopathies. We found that the depletion of L-arginine by overexpressing the metabolizing enzyme arginase 1 and arginine deiminase significantly reduced tau pathology in transgenic mouse models. We speculate that these effects associate with increased autophagy through amino acid sensing. G protein-coupled receptor (GPCR), family C, group 6, member A (GPRC6A) was deorphanized by binding to basic L-α amino acids, like L-arginine. We hypothesize that decreased GPRC6A signaling inhibits mTORC1 activation and thus promoting autophagy to induce tau clearance in tauopathies. We posit that GPRC6A remains tonically activated and senses extracellular amino acids sufficiency of L-α amino acids, especially becomes more sensitive to L-arginine in tauopathies.