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

Sarah M Waldherr,Nicole F Liachko,Brian C Kraemer,Timothy J Strovas,Taylor A Vadset

doi:10.1038/s41467-019-12070-3

Abstract

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 (UPRER) promotes clearance of pathological tau, and loss of the three UPRER branches differentially affects tauopathy phenotypes. Loss of function of xbp-1 and atf-6 genes, the two main UPRER 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 UPRER participate in amelioration of tauopathy by constitutively active XBP-1, possibly through endoplasmic reticulum-associated protein degradation (ERAD). Understanding how the UPRER modulates pathological tau accumulation will inform neurodegenerative disease mechanisms.

Highlights

To endure over the organismal lifespan, neurons utilize multiple strategies to achieve protein homeostasis
The unfolded protein response (UPRER) consists of three branches that regulate signaling to the nucleus and control the responses to unfolded protein within the endoplasmic reticulum (ER) lumen (Fig. 1a)
Using the genetically tractable model organism C. elegans, we examined the effects of loss of function mutations ablating signaling through each of the three branches of the UPRER [pek-1 (−/−), atf-6 (−/−), and xbp-1 (−/−)] on tau-mediated behavioral dysfunction in a mild model of human wildtype tau toxicity, which will be referred to as Tau transgenic C. elegans[20]

Summary

Introduction

To endure over the organismal lifespan, neurons utilize multiple strategies to achieve protein homeostasis (proteostasis). Proteostasis imbalance in the ER triggers the UPRER, which causes the molecular chaperone binding immunoglobulin protein (BiP) to dissociate from the three ER transmembrane stress sensors [protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 α (IRE1α), and activating transcription factor 6 (ATF6)] (Fig. 1a). IRE1α catalyzes non-canonical splicing of X-box binding protein 1 (XBP1) mRNA into the constitutively active form XBP1s, which becomes the master UPRER transcription factor controlling a wide range of gene targets required for ER proteostasis. These include genes related to protein folding, ER-. Activated IRE1α catalyzes the excision of a short non-canonical intron from

Methods

Results

Conclusion