A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration
Open accessAbstract
Hyperphosphorylation of the microtubule associated protein tau is detected in the brains of individuals with a range of neurodegenerative diseases including Alzheimer's disease (AD). An imbalance in phosphorylation and/or dephosphorylation of tau at disease-related sites has been suggested to initiate the abnormal metabolism and toxicity of tau in disease pathogenesis. However, the mechanisms underlying abnormal phosphorylation of tau in AD are not fully understood. Here, we show that the DNA damage-activated Checkpoint kinase 2 (Chk2) is a novel tau kinase and enhances tau toxicity in a transgenic Drosophila model. Overexpression of Drosophila Chk2 increases tau phosphorylation at Ser262 and enhances tau-induced neurodegeneration in transgenic flies expressing human tau. The non-phosphorylatable Ser262Ala mutation abolishes Chk2-induced enhancement of tau toxicity, suggesting that the Ser262 phosphorylation site is involved in the enhancement of tau toxicity by Chk2. In vitro kinase assays revealed that human Chk2 and a closely related checkpoint kinase 1 (Chk1) directly phosphorylate human tau at Ser262. We also demonstrate that Drosophila Chk2 does not modulate the activity of the fly homolog of microtubule affinity regulating kinase, which has been shown to be a physiological tau Ser262 kinase. Since accumulation of DNA damage has been detected in the brains of AD patients, our results suggest that the DNA damage-activated kinases Chk1 and Chk2 may be involved in tau phosphorylation and toxicity in the pathogenesis of AD.
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DDR proteins CHEK1 and CHEK2 have been shown to phosphorylate tau protein and contribute to its accumulation.
“In particular, DDR proteins CHEK1 and CHEK2 have been shown to phosphorylate tau protein, and contribute to its accumulation [65].”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [65]
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- Authors
- Iijima-Ando, K., Zhao, L., Gatt, A., Shenton, C., & Iijima, K.
- Affiliations
- Thomas Jefferson University (US)
- Corresponding author
- Iijima, Koichi
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-02-16
- Volume
- 19
- Issue
- 10
- Pages
- 1930-1938
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC2860892
- OpenAlex
- W2135133102
- Cited by
- 72
- References
- 83
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 2 · 2020: 9 · 2019: 5 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 7 · 2014: 6 · 2013: 4 · 2012: 4
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (NIRG-08-91985)
- American Federation for Aging Research
- Thomas Jefferson University
- National Institute on Aging (R01AG032279, R01AG032279-A1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau phosphorylation, Chk2, Chk1, DNA damage checkpoint, Alzheimer's disease, tau kinases, Drosophila model, tau toxicity
- MeSH terms
- Checkpoint Kinase 1, Animals, DNA Damage, Drosophila melanogaster, Enzyme Activation, Humans, Mutation, Nerve Degeneration, Phosphorylation, Phosphoserine, Protein Kinases, Recombinant Proteins, Retinal Degeneration, tau Proteins, Protein Serine-Threonine Kinases, Checkpoint Kinase 2
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