Down-regulation of WW domain-containing oxidoreductase induces Tau phosphorylation in vitro: A potential role in Alzheimer's disease

Chun I. Sze, Meng Su, Subbiah Pugazhenthi, Purevsuren Jambal, Li Jin Hsu, John Heath, Lori Schultz, Nan Shan Chang

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92 Citations (Scopus)

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 Ser 515/Ser516, enhanced phosphorylation of glycogen synthase kinase 3β (GSK-3β) and ERK, and enhanced NFT formation. Also an increased binding of phospho-GSK-3β with phospho-Tau was observed in these WOX1 knock-down cells. In comparison, increased phosphorylation of Tau, GSK-3β, 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-3β in neurons and cultured cells. 17β-Estradiol, a neuronal protective hormone, increased the binding of WOX1 and GSK-3β 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.

Original languageEnglish
Pages (from-to)30498-30506
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number29
DOIs
Publication statusPublished - 2004 Jul 16

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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