Down-regulation of WW Domain-containing Oxidoreductase Induces Tau Phosphorylation in Vitro
Open accessAbstract
Numerous enzymes hyperphosphorylate Tau in vivo, leading to the formation of neurofibrillary tangles (NFTs) in the neurons of Alzheimer's disease (AD). Compared with age-matched normal controls, we demonstrated here that the protein levels of WW domain-containing oxidoreductase WOX1 (also known as WWOX or FOR), its Tyr33-phosphorylated form, and WOX2 were significantly down-regulated in the neurons of AD hippocampi. Remarkably knock-down of WOX1 expression by small interfering RNA in neuroblastoma SK-N-SH cells spontaneously induced Tau phosphorylation at Thr212/Thr231 and Ser515/Ser516, enhanced phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) and ERK, and enhanced NFT formation. Also an increased binding of phospho-GSK-3beta with phospho-Tau was observed in these WOX1 knock-down cells. In comparison, increased phosphorylation of Tau, GSK-3beta, and ERK, as well as NFT formation, was observed in the AD hippocampi. Activation of JNK1 by anisomycin further increased Tau phosphorylation, and SP600125 (a JNK inhibitor) and PD-98059 (an MEK1/2 inhibitor) blocked Tau phosphorylation and NFT formation in these WOX1 knock-down cells. Ectopic or endogenous WOX1 colocalized with Tau, JNK1, and GSK-3beta in neurons and cultured cells. 17Beta-estradiol, a neuronal protective hormone, increased the binding of WOX1 and GSK-3beta with Tau. Mapping analysis showed that WOX1 bound Tau via its COOH-terminal short-chain alcohol dehydrogenase/reductase domain. Together WOX1 binds Tau via its short-chain alcohol dehydrogenase/reductase domain and is likely to play a critical role in regulating Tau hyperphosphorylation and NFT formation in vivo.
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WWOX may play a role in Alzheimer's disease through its interaction with tau.
“WWOX may play a role in Alzheimer’s disease through its interaction with tau28,29”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [29]
WWOX has been implicated in several neurological phenotypes; it binds tau and may play a critical role in regulating tau hyper-phosphorylation, neurofibrillary formation and Aβ aggregation.
“WWOX has been implicated in several neurological phenotypes96; in addition, it binds tau and may play a critical role in regulating tau hyper-phosphorylation, neurofibrillary formation and Aβ aggregation28,29.”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [29]
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Self-citation
- Authors
- Sze, C.-I., Su, M., Pugazhenthi, S., Jambal, P., Hsu, L.-J., Heath, J., Schultz, L., & Chang, N.-S.
- Affiliations
- Guthrie Foundation (US)
- Corresponding author
- Chang, Nan-Shan
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-07
- Volume
- 279
- Issue
- 29
- Pages
- 30498-30506
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1987972154
- Cited by
- 130
- References
- 59
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 6 · 2020: 10 · 2019: 8 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 8 · 2014: 9 · 2013: 4 · 2012: 7
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- American Heart Association
- National Cheng Kung University
- National Institutes of Health
- 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
- WOX1, WWOX, WOX2, tau phosphorylation, neurofibrillary tangles, Alzheimer's disease, GSK3β, ERK, JNK1, protein-protein interaction, hippocampus, estradiol, SK-N-SH cells, gene knockdown
- MeSH terms
- Glycogen Synthase Kinase 3 beta, WW Domain-Containing Oxidoreductase, Alzheimer Disease, Animals, Anisomycin, Anthracenes, Brain, Cell Line, Enzyme Inhibitors, Estradiol, Flavonoids, Genetic Vectors, Hippocampus, Humans, Immunohistochemistry, Microscopy, Fluorescence, Neurons, Oxidoreductases, Phosphorylation, Precipitin Tests, Protein Binding, Retroviridae, Serine, Temperature, Threonine, Time Factors, Tyrosine, Down-Regulation, tau Proteins, Protein Structure, Tertiary, COS Cells, Two-Hybrid System Techniques, Mitogen-Activated Protein Kinases, Tumor Suppressor Proteins, RNA, Small Interfering, Glycogen Synthase Kinase 3, Cell Line, Tumor, Mice, In Vitro Techniques
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