Bidirectional interplay of HSF1 degradation and UPR activation promotes tau hyperphosphorylation

Research output: Contribution to journalArticle

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Abstract

The unfolded protein response (UPR) in the endoplasmic reticulum (ER) and the cytoplasmic heat stress response are two major stress response systems necessary for maintaining proteostasis for cellular health. Failure of either of these systems, such as in sustained UPR activation or in insufficient heat shock response activation, can lead to the development of neurodegeneration. Alleviation of ER stress and enhancement of heat shock response through heat shock factor 1 (HSF1) activation have previously been considered as attractive potential therapeutic targets for Alzheimer’s disease (AD)—a prevalent and devastating tauopathy. Understanding the interplay of the two aforementioned systems and their cooperative role in AD remain elusive. Here we report studies in human brain and tau pathogenic mouse models (rTg4510, PS19, and rTg21221), identifying HSF1 degradation and UPR activation as precursors of aberrant tau pathogenesis. We demonstrate that chemical ER stress inducers caused autophagy-lysosomal HSF1 degradation, resulting in tau hyperphosphorylation in rat primary neurons. In addition, permanent HSF1 loss reversely causes chronic UPR activation, leading to aberrant tau phosphorylation and aggregation in the hippocampus of aged HSF1 heterozygous knock-out mice. The deleterious interplay of UPR activation and HSF1 loss is exacerbated in N2a cells stably overexpressing a pro-aggregation mutant TauRDΔK280 (N2a-TauRDΔK280). We provide evidence of how these two stress response systems are intrinsically interweaved by showing that the gene encoding C/EBP-homologous protein (CHOP) activation in the UPR apoptotic pathway facilitates HSF1 degradation, which likely further contributes to prolonged UPR via ER chaperone HSP70 a5 (BiP/GRP78) suppression. Upregulating HSF1 relieves the tau toxicity in N2a-TauRDΔK280 by reducing CHOP and increasing HSP70 a5 (BiP/GRP78). Our work reveals how the bidirectional crosstalk between the two stress response systems promotes early tau pathology and identifies HSF1 being one likely key player in both systems.

Original languageEnglish (US)
Article numbere1006849
JournalPLoS genetics
Volume13
Issue number7
DOIs
StatePublished - Jul 1 2017

Fingerprint

unfolded protein response
Unfolded Protein Response
heat shock
heat stress
Shock
Hot Temperature
degradation
protein
Heat-Shock Response
endoplasmic reticulum
Transcription Factor CHOP
stress response
Endoplasmic Reticulum Stress
Alzheimer disease
Endoplasmic Reticulum
Alzheimer Disease
Tauopathies
autophagy
Autophagy
hippocampus

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Bidirectional interplay of HSF1 degradation and UPR activation promotes tau hyperphosphorylation. / Kim, Eunhee; Sakata, Kazuko; Liao, Francesca-Fang.

In: PLoS genetics, Vol. 13, No. 7, e1006849, 01.07.2017.

Research output: Contribution to journalArticle

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