Cited by 130Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Down-regulation of WW Domain-containing Oxidoreductase Induces Tau Phosphorylation in Vitro

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Sze, Chun-I, Su, Meng, Pugazhenthi, Subbiah, Jambal, Purevsuren, Hsu, Li-Jin, Heath, John, Schultz, Lori, Chang, Nan-Shan·2004·Journal of Biological Chemistry

Abstract

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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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
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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