title: The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress.
abstract: The unfolded protein response (UPR) is activated in neurodegenerative tauopathies such as Alzheimer's disease (AD) in close connection with early stages of tau pathology. Metabolic disturbances are strongly associated with increased risk for AD and are a potent inducer of the UPR. Here, we demonstrate that metabolic stress induces the phosphorylation of endogenous tau via activation of the UPR. Strikingly, upon restoration of the metabolic homeostasis, not only the levels of the UPR markers pPERK, pIRE1α and BiP, but also tau phosphorylation are reversed both in cell models as well as in torpor, a physiological hypometabolic model in vivo. Intervention in the UPR using the global UPR inhibitor TUDCA or a specific small-molecule inhibitor of the PERK signaling pathway, inhibits the metabolic stress-induced phosphorylation of tau. These data support a role for UPR-mediated tau phosphorylation as part of an adaptive response to metabolic stress. Failure to restore the metabolic homeostasis will lead to prolonged UPR activation and tau phosphorylation, and may thus contribute to AD pathogenesis. We demonstrate that the UPR is functionally involved in the early stages of tau pathology. Our data indicate that targeting of the UPR may be employed for early intervention in tau-related neurodegenerative diseases.
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: van der Harg
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Nölle
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Zwart
authors.affiliation: Units of Chronobiology and Molecular Neurobiology, Center for Behaviour and Neurosciences, University of Groningen, Groningen, The Netherlands.
authors.forename: A S
authors.initials: AS
authors.lastname: Boerema
authors.affiliation: Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E S
authors.initials: ES
authors.lastname: van Haastert
authors.affiliation: Units of Chronobiology and Molecular Neurobiology, Center for Behaviour and Neurosciences, University of Groningen, Groningen, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Strijkstra
authors.affiliation: Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: J Jm
authors.initials: JJ
authors.lastname: Hoozemans
authors.affiliation: 1] Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands [2] Department of Clinical Genetics and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands [3] Departments of Functional Genomics and Molecular and Cellular Neuroscience, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Scheper
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000378:metabolism; D003080:Cold Temperature; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D003847:Deoxyglucose / Q000633:toxicity; D004722:Endoribonucleases / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D013655:Taurochenodeoxycholic Acid / Q000633:toxicity; D014415:Tunicamycin / Q000633:toxicity; D056811:Unfolded Protein Response / Q000187:drug effects; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D014415:Tunicamycin; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D003847:Deoxyglucose; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases