Characterizing Transcriptional Activation of the Endoplasmic Reticulum Unfolded Protein Response in Caenorhabditis elegans Models of Tau Pathology

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. Age-associated changes in neuronal proteostasis dynamics occur in neurodegenerative diseases. Under physiological conditions, tau protein in the cytoplasm modulates microtubule dynamics necessary for structural and regulatory functions in neurons. Under pathological conditions, abnormal tau protein species contribute to a group of neurodegenerative diseases known as tau proteinopathies (tauopathies) To identify pathways protecting neurons from pathological tau protein, I employ a transgenic Caenorhabditis elegans (C. elegans) model of human tauopathy exhibiting proteostatic disruption. I 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-1s 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). Given the importance of UPRER transcriptional regulation, I conduct transcriptomic analysis to enrich for neuronal transcripts and nominate five XBP-1s target genes with human orthologs and an association with ATF6 (csp-1, dnj-28, hsp-4, ckb-2, and lipl-3). CSP-1, DNJ-28, HSP-4, and LIPL-3 function are necessary for XBP-1s-mediated tauopathy suppression. Furthermore, functional HSP-4 modulates tauopathy phenotypes. Understanding how the UPRER modulates pathological tau accumulation will inform neurodegenerative disease mechanisms and directed studies in mammalian systems with the long-term goal of identifying therapeutic targets in human tauopathies.