Bidirectional interplay of HSF1 degradation and UPR activation promotes tau hyperphosphorylation

• Published in: PLoS genetics Vol. 13; no. 7; p. e1006849
• Main Authors: Kim, Eunhee, Sakata, Kazuko, Liao, Francesca-Fang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.07.2017; Public Library of Science (PLoS)
• Subjects: Activation; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Animal models; Animals; Apoptosis; Autophagy - genetics; Bidirectional; Biochemistry; Biology and Life Sciences; Brain; CCAAT/enhancer-binding protein; Cognitive ability; Dementia; Departments; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Gene Expression Regulation; Genetic aspects; Health aspects; Heat shock factors; Heat Shock Transcription Factors; Heat stress; Heat-Shock Proteins - genetics; Heat-Shock Response - genetics; Hippocampus - metabolism; Hippocampus - pathology; Homeostasis; Homology; HSF1 protein; Hsp70 protein; Humans; Huntingtons disease; Inducers; Kinases; Knock; Medicine and Health Sciences; Mice; Mice, Knockout; Neural circuitry; Neurobiology; Neurodegeneration; Neurodegenerative diseases; Neurons - metabolism; Neurons - pathology; Neurosciences; Pathogenesis; Pathology; Phagocytosis; Pharmacology; Phosphorylation; Protein Aggregation, Pathological - genetics; Protein folding; Proteins; Proteolysis; Rats; Research and Analysis Methods; Stress response; Tau protein; Tau proteins; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - genetics; Tauopathies - metabolism; Tauopathies - pathology; Toxicity; Transcription Factor CHOP - biosynthesis; Transcription Factor CHOP - genetics; Transcription Factors - biosynthesis; Transcription Factors - genetics; Unfolded Protein Response - genetics; United States > US; Tennessee
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006849

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 TauRD ΔK280 (N2a-TauRD ΔK280). 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-TauRD ΔK280 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.