title: Folate deficiency-induced oxidative stress contributes to neuropathy in young and aged zebrafish--implication in neural tube defects and Alzheimer's diseases.
abstract: Folate is a nutrient essential for the development, function and regeneration of nervous systems. Folate deficiency has been linked to many neurological disorders including neural tube defects in fetus and Alzheimer's diseases in the elderly. However, the etiology underlying these folate deficiency-associated diseases is not completely understood. In this study, zebrafish transgenic lines with timing and duration-controllable folate deficiency were developed by ectopically overexpressing a recombinant EGFP-γ-glutamyl hydrolase (γGH). Impeded neural crest cell migration was observed in the transgenic embryos when folate deficiency was induced in early stages, leading to defective neural tube closure and hematopoiesis. Adding reduced folate or N-acetylcysteine reversed the phenotypic anomalies, supporting the causal link between the increased oxidative stress and the folate deficiency-induced abnormalities. When folate deficiency was induced in aged fish accumulation of beta-amyloid and phosphorylated Tau protein were found in the fish brain cryo-sections. Increased autophagy and accumulation of acidic autolysosome were apparent in folate deficient neuroblastoma cells, which were reversed by reduced folate or N-acetylcysteine supplementation. Decreased expression of cathepsin B, a lysosomal protease, was also observed in cells and tissue with folate deficiency. We concluded that folate deficiency-induced oxidative stress contributed to the folate deficiency-associated neuropathogenesis in both early and late stages of life.
authors.affiliation: The Institute of Basic Medical Science, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tseng-Ting
authors.initials: TT
authors.lastname: Kao
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Chu
authors.affiliation: The Institute of Basic Medical Science, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Gang-Hui
authors.initials: GH
authors.lastname: Lee
authors.affiliation: The Institute of Basic Medical Science, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tsun-Hsien
authors.initials: TH
authors.lastname: Hsiao
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Nai-Wei
authors.initials: NW
authors.lastname: Cheng
authors.affiliation: The Institute of Basic Medical Science, National Cheng Kung University, Tainan, Taiwan; Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Nan-Shan
authors.initials: NS
authors.lastname: Chang
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Bing-Hung
authors.initials: BH
authors.lastname: Chen
authors.affiliation: The Institute of Basic Medical Science, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan. Electronic address: tffu@mail.ncku.edu.tw.
authors.forename: Tzu-Fun
authors.initials: TF
authors.lastname: Fu
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism / Q000494:pharmacology; D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D004625:Embryo, Nonmammalian; D005492:Folic Acid / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000150:complications / Q000235:genetics / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006358:Hot Temperature / Q000009:adverse effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009432:Neural Crest / Q000502:physiology; D009436:Neural Tube Defects / Q000209:etiology* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D013997:Time Factors; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D011623:gamma-Glutamyl Hydrolase / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; D029961:Zebrafish Proteins; C485184:enhanced green fluorescent protein; C542260:map1lc3b protein, zebrafish; D049452:Green Fluorescent Proteins; D005492:Folic Acid; D011623:gamma-Glutamyl Hydrolase; D002401:Cathepsin B; D000111:Acetylcysteine
keywords: Alzheimer's diseases; Folate deficiency; Neural tube defects; One-carbon metabolism; Zebrafish; γ-Glutamyl hydrolase