ArticleCell death & disease2014
The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress.
Article in Cell death & disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 87 citations in OpenAlex.
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- Exercise modulation of gut microbiota in Alzheimer's disease: pathophysiological mechanisms and therapeutic perspectives.Frontiers in aging neuroscience · 2025Review
- The Mechanistic Link Between Tau-Driven Proteotoxic Stress and Cellular Senescence in Alzheimer's Disease.International journal of molecular sciences · 2024Review
- Histone Methylation, Energy Metabolism, and Alzheimer's Disease.Aging and disease · 2024Review
- Emerging Roles of Bile Acids and TGR5 in the Central Nervous System: Molecular Functions and Therapeutic Implications.International journal of molecular sciences · 2024Review
- Mind the Metabolic Gap: Bridging Migraine and Alzheimer's disease through Brain Insulin Resistance.Aging and disease · 2024Review
- Torpor induces reversible tau hyperphosphorylation and accumulation in mice expressing human tau.Acta neuropathologica communications · 2024Article
- Modeling Alzheimer's disease using human cell derived brain organoids and 3D models.Frontiers in neuroscience · 2024Review
- The PERK pathway: beneficial or detrimental for neurodegenerative diseases and tumor growth and cancer.Human molecular genetics · 2023Review
- Connecting the Gut Microbiota and Neurodegenerative Diseases: the Role of Bile Acids.Molecular neurobiology · 2023Review
- Roles of bile acids signaling in neuromodulation under physiological and pathological conditions.Cell & bioscience · 2023Review
- Acute Pharmacological Inhibition of Protein Kinase R-Like Endoplasmic Reticulum Kinase Signaling After Spinal Cord Injury Spares Oligodendrocytes and Improves Locomotor Recovery.Journal of neurotrauma · 2023Article
- New Insights into the Molecular Interplay between Human Herpesviruses and Alzheimer's Disease-A Narrative Review.Brain sciences · 2022Review
- Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases.Translational neurodegeneration · 2022Review
- Evidence against a contribution of the CCAAT-enhancer binding protein homologous protein (CHOP) in mediating neurotoxicity in rTg4510 mice.Scientific reports · 2022Article
- Activating transcription factor 4-dependent lactate dehydrogenase activation as a protective response to amyloid beta toxicity.Brain communications · 2021Article
- The UPR in Neurodegenerative Disease: Not Just an Inside Job.Biomolecules · 2020Review
- Alterations in Tau Metabolism in ALS and ALS-FTSD.Frontiers in neurology · 2020Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.