title: Identification of key uric acid synthesis pathway in a unique mutant silkworm Bombyx mori model of Parkinson's disease.
abstract: Plasma uric acid (UA) levels decrease following clinical progression and stage development of Parkinson's disease (PD). However, the molecular mechanisms underlying decreases in plasma UA levels remain unclear, and the potential to apply mutagenesis to a PD model has not previously been discovered. We identified a unique mutant of the silkworm Bombyx mori (B.mori) op. Initially, we investigated the causality of the phenotypic "op" by microarray analysis using our constructed KAIKO functional annotation pipeline. Consequently, we found a novel UA synthesis-modulating pathway, from DJ-1 to xanthine oxidase, and established methods for large-scale analysis of gene expression in B. mori. We found that the mRNA levels of genes in this pathway were significantly lower in B. mori op mutants, indicating that downstream events in the signal transduction cascade might be prevented. Additionally, levels of B.mori tyrosine hydroxylase (TH) and DJ-1 mRNA were significantly lower in the brain of B. mori op mutants. UA content was significantly lower in the B. mori op mutant tissues and hemolymph. The possibility that the B. mori op mutant might be due to loss of DJ-1 function was supported by the observed vulnerability to oxidative stress. These results suggest that UA synthesis, transport, elimination and accumulation are decreased by environmental oxidative stress in the B. mori op mutant. In the case of B. mori op mutants, the relatively low availability of UA appears to be due both to the oxidation of DJ-1 and to its expenditure to mitigate the effects of environmental oxidative stress. Our findings are expected to provide information needed to elucidate the molecular mechanism of decreased plasma UA levels in the clinical stage progression of PD.
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan. h_tabuno@cc.tuat.ac.jp
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tabunoki
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Ono
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ode
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Natsuki
authors.initials: N
authors.lastname: Kawana
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Banno
authors.forename: Toru
authors.initials: T
authors.lastname: Shimada
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kimiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Satoh
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Bono
mesh_terms: D000818:Animals; D012831:Bombyx; D004195:Disease Models, Animal; D009154:Mutation; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D014527:Uric Acid / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000235:genetics
chemical_list: D014527:Uric Acid; D014446:Tyrosine 3-Monooxygenase; D014969:Xanthine Oxidase
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