Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function
Open accessAbstract
The presence of tangles composed of phosphorylated tau is one of the neuropathological hallmarks of Alzheimer's disease (AD). Tau, a microtubule (MT)-associated protein, accumulates in AD potentially as a result of posttranslational modifications, such as hyperphosphorylation and conformational changes. However, it has not been fully understood how tau accumulation and phosphorylation are deregulated. In the present study, we identified a novel role of death-associated protein kinase 1 (DAPK1) in the regulation of the tau protein. We found that hippocampal DAPK1 expression is markedly increased in the brains of AD patients compared with age-matched normal subjects. DAPK1 overexpression increased tau protein stability and phosphorylation at multiple AD-related sites. In contrast, inhibition of DAPK1 by overexpression of a DAPK1 kinase-deficient mutant or by genetic knockout significantly decreased tau protein stability and abolished its phosphorylation in cell cultures and in mice. Mechanistically, DAPK1-enhanced tau protein stability was mediated by Ser71 phosphorylation of Pin1, a prolyl isomerase known to regulate tau protein stability, phosphorylation, and tau-related pathologies. In addition, inhibition of DAPK1 kinase activity significantly increased the assembly of MTs and accelerated nerve growth factor-mediated neurite outgrowth. Given that DAPK1 has been genetically linked to late onset AD, these results suggest that DAPK1 is a novel regulator of tau protein abundance, and that DAPK1 upregulation might contribute to tau-related pathologies in AD. Therefore, we offer that DAPK1 might be a novel therapeutic target for treating human AD and other tau-related pathologies.
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UV irradiation induces DAPK1 to phosphorylate Pin1 at Ser71, inactivating its isomerase activity.
“UV irradiation induces DAPK1 to phosphorylate Pin1 at Ser71, thus inactivating the isomerase activity 49, 50.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [49]
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- Authors
- Kim, B. M., You, M.-H., Chen, C.-H., Lee, S., Hong, Y., Hong, Y., Kimchi, A., Zhou, X. Z., & Lee, T. H.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Inje University (KR)
- Weizmann Institute of Science (IL)
- Corresponding author
- Lee, T H
- Venue
- Cell Death & Disease
- Published
- 2014-05-22
- Volume
- 5
- Issue
- 5
- Pages
- e1237-e1237
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC4047864
- OpenAlex
- W1985025450
- Cited by
- 98
- References
- 62
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 14 · 2023: 9 · 2022: 8 · 2021: 7 · 2020: 10 · 2019: 5 · 2018: 11 · 2017: 4 · 2016: 9 · 2015: 8 · 2014: 2
- FWCI
- 5.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Death and Disease (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Alzheimer's Association
- American Federation for Aging Research
- National Research Foundation
- Inje University
- National Institutes of Health
- National Institute on Aging (R00AG033104, P50 AG05134, T32AG023480, P50AG005134)
- National Institute of Mental Health (R24MH068855)
- 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
- DAPK1, tau protein, tau hyperphosphorylation, Pin1, peptidyl-prolyl isomerase, Alzheimer's disease, microtubule assembly, neurite outgrowth, nerve growth factor, hippocampus, therapeutic target
- MeSH terms
- NIMA-Interacting Peptidylprolyl Isomerase, Age Factors, Alzheimer Disease, Animals, Brain, HeLa Cells, Humans, Mutation, Neurons, Phosphorylation, Time Factors, Transfection, Case-Control Studies, Neurites, PC12 Cells, tau Proteins, Mice, Knockout, Peptidylprolyl Isomerase, RNA Interference, NIH 3T3 Cells, Mice, Rats, Protein Stability, HEK293 Cells, Death-Associated Protein Kinases
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