Plasma the crystals (UA) levels decrease following clinical progression and stage development of Parkinson’s disease (PD). to loss of DJ-1 function was supported by the observed vulnerability to ITPKB oxidative stress. SKF 89976A HCl These results suggest that UA synthesis transport elimination and accumulation are decreased by environmental oxidative stress in the mutant. In the case of 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. Introduction Parkinson’s disease (PD) is a common neurodegenerative disorder with an etiology involving oxygen radicals and other oxidants that attack dopaminergic neuronal cells and which damage and deplete dopamine levels [1]. Genetic studies have identified 18 genes associated with PD at different loci based on family linkage analysis (PD; Online Mendelian Inheritance in Man (OMIM) 168600). PD-associated gene knockout animal models have been developed as familial PD models [2]. The majority of idiopathic PD cases however are the result of sporadic onset caused by environmental stress [3] and a molecular-based mechanism of oxidative stress has been developed. In animal models of sporadic PD oxidative stress has been simulated using parkinsonian neurotoxins that are mitochondrial complex I inhibitors [4] namely 1-methyl-4-phenyl-1 2 3 6 (MPTP) 6 (6-OHDA) paraquat (PQ) and rotenone (ROT). The final product of purine metabolism uric acid SKF 89976A HCl (UA) plays an important role as a physiological antioxidant [5]. In recent years several groups have reported the correlation between decreased plasma UA levels and neuron cell failure in the substantia nigra clinical progression and stage of PD [6] [7] [8] [9] [10]. Conversely high plasma UA concentrations in hyperuricemia may reduce the risk and delay the progression of PD [11]. Plasma UA might be expended to resist oxidative injury in PD but the molecular mechanism underlying the decrease in plasma UA in advanced clinical stages of PD has not been analyzed using either of these models. Here we used a silkworm mutant with reduced levels of UA to examine the mechanisms involved in UA metabolism. In silkworms UA is mainly synthesized in the fat body from where it is transported to the integument via the hemolymph. On the SKF 89976A HCl other hand UA is eliminated through the Malpighian tubules. UA accumulates as urate granules which cause a whitening of the integument color [12]. UA is typically the ultimate SKF 89976A HCl metabolite in insects but in UA is partly converted to urea by urate oxidase [13]. Mutant larvae unable to synthesize UA due to a deficiency in xanthine oxidase (XD/XO) [14] [15] [16] or failure of the UA transporter [17] cannot accumulate UA in the larval epidermis and take on a translucent appearance. The mutant exhibits spontaneous and pronounced translucency during the larval stage (Fig. 1) and occasional unique actions such as vibration (Video S1). Figure 1 Phenotypes of and wild-type larvae. Classical linkage analysis has demonstrated that a mutation located on chromosome 23 is responsible for the extraordinarily high phenotype mortality particularly in the pupal stage as well as male infertility (NBRP silkworm database: http://www.shigen.nig.ac.jp/silkwormbase/). Despite the unique phenotypes of the mutant with reduced levels of UA the causative gene and position has not been clarified. In the present study we characterized the mutant and identified the novel uric acid synthesis pathway using microarray analysis. Results Screening for Target Molecules using Microarray We investigated the number of human homologs in the genome. We identified 8096 human homologs among 14 623 total transcripts in the consensus gene set by merging all the gene sets using GLEAN (http://sgp.dna.affrc.go.jp/pubdata/genomicsequences.html). Furthermore enrichment analysis of the human homologs (Table S1) showed that the conserved human homologs in that showed the.