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Cell Death Dis. 2014 Aug 28;5:e1393. doi: 10.1038/cddis.2014.354.

The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress.

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  • 1Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
  • 2Units of Chronobiology and Molecular Neurobiology, Center for Behaviour and Neurosciences, University of Groningen, Groningen, The Netherlands.
  • 3Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
  • 41] 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.


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.

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