Exploring non-autonomous protein homeostasis driven by glutamatergic neurons

Neuronal overexpression of xbp-1 s , a regulator of the endoplasmic reticulum unfolded protein response (UPR ^ER ), induces non-autonomous UPR ^ER activation in distal tissues of Caenorhabditis elegans . Specific neuronal subtypes, including glutamatergic, octopaminergic, and GABAergic neurons, have been implicated in enhancing intestinal proteostasis. Here, we investigated the mechanisms underlying this effect. Glutamatergic xbp-1 s mediated proteostasis improvement was independent of endogenous xbp-1 but required the transcription factor HLH-30 , potentially via autophagy and ER-associated degradation pathways. In contrast, octopaminergic and GABAergic signaling yielded limited insight. These findings highlight the complexity of neuronal control of organismal proteostasis through non-autonomous UPR ^ER signaling pathways.