RRC ID 59619
Author Waldherr SM, Strovas TJ, Vadset TA, Liachko NF, Kraemer BC.
Title Constitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau.
Journal Nat Commun
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.
Volume 10(1)
Pages 4443
Published 2019-9-30
DOI 10.1038/s41467-019-12070-3
PII 10.1038/s41467-019-12070-3
PMID 31570707
PMC PMC6768869
MeSH Animals Animals, Genetically Modified Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Carrier Proteins / genetics Carrier Proteins / metabolism Endoplasmic Reticulum / metabolism* Endoplasmic Reticulum-Associated Degradation Homeostasis Humans Models, Animal Neurodegenerative Diseases / metabolism* Neurons / metabolism Phenotype Tauopathies / metabolism Transcription Factors / genetics Transcription Factors / metabolism Unfolded Protein Response / physiology* X-Box Binding Protein 1 / genetics X-Box Binding Protein 1 / metabolism* eIF-2 Kinase / metabolism tau Proteins / adverse effects tau Proteins / metabolism*
IF 11.878
Times Cited 3
C.elegans tm1153