Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan.
PLoS One. 2013 Jul 24;8(7):e69130. doi: 10.1371/journal.pone.0069130. Print 2013.
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.
血浆尿酸（UA）水平在帕金森病（PD）的临床进展和阶段发展后降低。然而，血浆 UA 水平降低的分子机制尚不清楚，并且以前尚未发现将诱变应用于 PD 模型的潜力。我们鉴定了家蚕（Bombyx mori）的一个独特突变体 op。最初，我们使用我们构建的 KAIKO 功能注释管道通过微阵列分析来研究表型“op”的因果关系。结果，我们发现了一个从 DJ-1 到黄嘌呤氧化酶的新型 UA 合成调节途径，并建立了在家蚕中大规模分析基因表达的方法。我们发现该途径中基因的 mRNA 水平在家蚕 op 突变体中显着降低，表明信号转导级联中的下游事件可能被阻止。此外，家蚕 op 突变体脑中的 B.mori 酪氨酸羟化酶（TH）和 DJ-1 mRNA 水平显着降低。 UA 含量在家蚕 op 突变体组织和血淋巴中显着降低。家蚕 op 突变体可能由于 DJ-1 功能丧失，这一点得到了观察到的对氧化应激的脆弱性的支持。这些结果表明，在 B. mori op 突变体中，UA 的合成、转运、消除和积累减少是由环境氧化应激引起的。在 B. mori op 突变体的情况下，UA 的相对可用性较低似乎既归因于 DJ-1 的氧化，也归因于其支出以减轻环境氧化应激的影响。我们的研究结果有望提供阐明 PD 临床阶段进展中血浆 UA 水平降低的分子机制所需的信息。
