Arginine Sensor (CASTOR1) Dysfunction Drives Tauopathy

About This Grant

Abstract A common feature in many neurodegenerative diseases including Alzheimer’s disease (AD) and tauopathies comprise of slower protein turnover, lysosomal dysfunction, and the precipitation of protein aggregates. Although we know that neurometabolism impacts AD, it is unclear how nutrient sensors regulates tau proteostasis particularly at the level of the lysosome. The amino acid arginine is particularly compelling because recent evidence uncovered several molecular sensors of arginine within the cell that directs the mechanistic Target of Rapamycin (mTOR). Cellular Arginine Sensor for mTORC1 (CASTOR1) serves as a negative regulator of mTORC1 signaling. Two molecular switches inhibit CASTOR1 function including arginine and phosphorylation of CASTOR1. We identified increased gene transcripts for CASTOR1 together with protein expression in the hippocampus of AD compared to control brains. We also showed that AD brains with more CASTOR1 presented lower phospho-tau burden, counter to that of AD brains with lower CASTOR1 displaying higher phospho-tau loads. In mice with tauopathy arginine levels accumulate in plasma and brain but also increase CASTOR1. We demonstrate that induction of wild-type CASTOR1, increased lysosomal acidification, autophagy flux, and reduced PHF1 tau, whereas pseudo-mimetic S14D mutation impaired lysosomal function and failed to reduced tau to the same extent in cell models. We posit that CASTOR1 induction remains essential during proteotoxic stress to improve lysosomal function, repair, and promote aggregate clearance. We also posit that inadvertent phosphorylation of CASTOR1 impairs is function, promotes its degradation, decreases lysosomal function, and promotes tau toxicity. We will test how CASTOR1 mechanistically improves lysosomal function during proteotoxic stressors including tau, lysosomal damaging agents in cellular models. We will determine how proteotoxic stressors impair arginine metabolism and accumulation through novel FRET-based arginine biosensors. We will test how CASTOR1 loss of function impacts cognition, the tau phenotype, and neuronal tau spread using CASTOR1 knockout mice. This application tests: 1) nutrient (amino acid) sensors as therapeutic hubs to improve proteostasis during tauopathy; 2) how posttranslational modifications on nutrient sensors re-/ de-sensitize their function; 3) the causal link between arginine sensing/ signaling dysfunction and AD progression; 4) CASTOR1 as a potentially new therapeutic node and sensor for proteinopathies.