Arginine Sensor (CASTOR1) Dysfunction Drives Tauopathy
openNIA - National Institute on Aging
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.
Up to $424K
health research