ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 163 papers.
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Who cites it
163 citing papers in PubMed, 270 citations in OpenAlex.
- PERK deficiency amplifies molecular, structural, and network vulnerability to repetitive mild traumatic brain injury.Neurobiology of disease · 2026Article
- Fyn kinase: a key mechanistic regulator and therapeutic target in tauopathy and neurodegenerative diseases.Translational neurodegeneration · 2026Review
- The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.Cells · 2026Review
- Integrative genomic and functional analyses reveal NINL as a modulator of tau aggregation.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Progressive Supranuclear Palsy PERK Haplotype B Selectively Translates DLX1 Promoting Tau Toxicity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- PERK Deficiency Amplifies Molecular, Structural, and Network Vulnerability to Repetitive Mild Traumatic Brain Injury.bioRxiv : the preprint server for biology · 2026Article
- Therapeutic Options for Alzheimer's Disease and Aging-Associated Cognitive Decline: State of the Art in the ACH2.0 Paradigm.International journal of molecular sciences · 2026Review
- Integrative Genomic and Functional Analyses Reveal NINL as a Modulator of Tau Aggregation.bioRxiv : the preprint server for biology · 2025Article
- Probing tau citrullination in Alzheimer's disease brains and mouse models of tauopathy.Acta neuropathologica · 2025Article
- Derlin-3 manipulates the endoplasmic reticulum stress and IgG4 secretion of plasma cells in lung adenocarcinoma.Oncogene · 2025Article
- Review
- Immunoelectron microscopy and biochemical studies using three anti-tau antibodies in human brains: associations between pTau and ribosomes.Acta neuropathologica communications · 2025Article
- The many connections of UFMylation with Alzheimer's disease: a comprehensive review.Molecular neurodegeneration · 2025Review
- Testing Protein Stress Signals in Peripheral Immunocytes Under the Same Treatment Capable of Decreasing the Incidence of Alzheimer's Disease in Bladder Cancer Patients.Current issues in molecular biology · 2025Article
- Glucose starvation induces tau phosphorylation leading to cellular stress response in fission yeast.Archives of microbiology · 2025Article
- Insights into pathophysiology, biomarkers, and therapeutics in tauopathies: Proceedings of the Tau2024 Global Conference.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Alzheimer's Is a Multiform Disease of Sustained Neuronal Integrated Stress Response Driven by the C99 Fragment Generated Independently of AβPP; Proteolytic Production of Aβ Is Suppressed in AD-Affected Neurons: Evolution of a Theory.International journal of molecular sciences · 2025Review
- Article
- EDEM1 Inhibits Endoplasmic Reticulum Stress to Induce Doxorubicin Resistance through Accelerating ERAD and Activating Keap1/Nrf2 Antioxidant Pathway in Triple-Negative Breast Cancer.Research (Washington, D.C.) · 2025Article
- Organelle abnormalities in Alzheimer's disease.Organelle (Tucson, Ariz.) · 2025Article
103 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
In Alzheimer's disease (AD), the mechanisms of neuronal loss remain largely unknown. Although tau pathology is closely correlated with neuronal loss, how its accumulation may lead to activation of neurotoxic pathways is unclear. Here we show that tau increased the levels of ubiquitinated proteins in the brain and triggered activation of the unfolded protein response (UPR). This suggested that tau interferes with protein quality control in the endoplasmic reticulum (ER). Consistent with this, ubiquitin was found to associate with the ER in human AD brains and tau transgenic (rTg4510) mouse brains, but this was not always colocalized with tau. The increased levels of ubiquitinated protein were accompanied by increased levels of phosphorylated protein kinase R-like ER kinase (pPERK), a marker that indicates UPR activation. Depleting soluble tau levels in cells and brain could reverse UPR activation. Tau accumulation facilitated its deleterious interaction with ER membrane and associated proteins that are essential for ER-associated degradation (ERAD), including valosin-containing protein (VCP) and Hrd1. Based on this, the effects of tau accumulation on ERAD efficiency were evaluated using the CD3δ reporter, an ERAD substrate. Indeed, CD3δ accumulated in both in vitro and in vivo models of tau overexpression and AD brains. These data suggest that soluble tau impairs ERAD and the result is activation of the UPR. The reversibility of this process, however, suggests that tau-based therapeutics could significantly delay this type of cell death and therefore disease progression.
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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.