TY - JOUR
T1 - Down-regulation of WW domain-containing oxidoreductase induces Tau phosphorylation in vitro
T2 - A potential role in Alzheimer's disease
AU - Sze, Chun I.
AU - Su, Meng
AU - Pugazhenthi, Subbiah
AU - Jambal, Purevsuren
AU - Hsu, Li Jin
AU - Heath, John
AU - Schultz, Lori
AU - Chang, Nan Shan
PY - 2004/7/16
Y1 - 2004/7/16
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M401399200
DO - 10.1074/jbc.M401399200
M3 - Article
C2 - 15126504
AN - SCOPUS:3142710158
SN - 0021-9258
VL - 279
SP - 30498
EP - 30506
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 29
ER -