Waldherr SM et al. (2024) Commun Biol "Endoplasmic reticulum unfolded protein response transcriptional targets of XBP-1s mediate rescue from tauopathy."

Saxton AD, Wheeler JM, Vadset TA, Waldherr SM, Kraemer BC, Liachko NF, McMillan PJ, Han M

[Commun Biol, 2024]

Pathological tau disrupts protein homeostasis (proteostasis) within neurons in Alzheimer's disease (AD) and related disorders. We previously showed constitutive activation of the endoplasmic reticulum unfolded protein response (UPR^ER) transcription factor XBP-1s rescues tauopathy-related proteostatic disruption in a tau transgenic Caenorhabditis elegans (C. elegans) model of human tauopathy. XBP-1s promotes clearance of pathological tau, and loss of function of the ATF-6 branch of the UPR^ER prevents XBP-1s rescue of tauopathy in C. elegans. We conducted transcriptomic analysis of tau transgenic and xbp-1s transgenic C. elegans and found 116 putative target genes significantly upregulated by constitutively active XBP-1s. Among these were five candidate XBP-1s target genes with human orthologs and a previously known association with ATF6 (csp-1, dnj-28, hsp-4, ckb-2, and lipl-3). We examined the functional involvement of these targets in XBP-1s-mediated tauopathy suppression and found loss of function in any one of these genes completely disrupts XBP-1s suppression of tauopathy. Further, we demonstrate upregulation of HSP-4, C. elegans BiP, partially rescues tauopathy independent of other changes in the transcriptional network. Understanding how the UPR^ER modulates pathological tau accumulation will inform neurodegenerative disease mechanisms and direct further study in mammalian systems with the long-term goal of identifying therapeutic targets in human tauopathies.

Waldherr SM et al. (2019) Nat Commun "Constitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau."

Waldherr SM, Liachko NF, Strovas TJ, Kraemer BC, Vadset TA

[Nat Commun, 2019]

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.