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

Research output: Contribution to journalArticle

81 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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