Down-regulation of WW domain-containing oxidoreductase induces Tau phosphorylation in vitro. A potential role in Alzheimer's disease.
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.
Sze
Chun-I
CI
Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Su
Meng
M
Pugazhenthi
Subbiah
S
Jambal
Purevsuren
P
Hsu
Li-Jin
LJ
Heath
John
J
Schultz
Lori
L
Chang
Nan-Shan
NS
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D001921:Brain / Q000473:pathology; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005822:Genetic Vectors; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000737:chemistry*; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D012694:Serine / Q000737:chemistry; D013696:Temperature; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques; D014443:Tyrosine / Q000737:chemistry; D000074584:WW Domain-Containing Oxidoreductase; D016875:tau Proteins / Q000378:metabolism*
D000873:Anthracenes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D016875:tau Proteins; C432165:pyrazolanthrone; D013912:Threonine; D014443:Tyrosine; D012694:Serine; D004958:Estradiol; D000841:Anisomycin; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C428130:Wwox protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one