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To endure over the organismal lifespan, neurons utilize multiple strategies to achieve protein homeostasis (proteostasis). Some homeostatic mechanisms act in a subcellular compartment-specific manner, but others exhibit trans-compartmental mechanisms of proteostasis. To identify pathways protecting neurons from pathological tau protein, we employed a transgenic  Caenorhabditis elegans  model of human tauopathy exhibiting proteostatic disruption. We show normal functioning of the endoplasmic reticulum unfolded protein response (UPR ER ) promotes clearance of pathological tau, and loss of the three UPR ER  branches differentially affects tauopathy phenotypes. Loss of function of  xbp-1  and  atf-6  genes, the two main UPR ER  transcription factors, exacerbates tau toxicity. Furthermore, constitutive activation of master transcription factor XBP-1 ameliorates tauopathy phenotypes. However, both ATF6 and PERK branches of the UPR ER  participate in amelioration of tauopathy by constitutively active XBP-1, possibly through endoplasmic reticulum-associated protein degradation (ERAD). Understanding how the UPR ER  modulates pathological tau accumulation will inform neurodegenerative disease mechanisms.

Constitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau