Chronobiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, United Kingdom.
Preclinical, Imaging &Research Laboratories (PIRL), SAHMRI, Gilles Plains, Adelaide, Australia.
Sci Rep. 2017 Feb 22;7:43030. doi: 10.1038/srep43030.
The pronounced cachexia (unexplained wasting) seen in Huntington's disease (HD) patients suggests that metabolic dysregulation plays a role in HD pathogenesis, although evidence of metabolic abnormalities in HD patients is inconsistent. We performed metabolic profiling of plasma from presymptomatic HD transgenic and control sheep. Metabolites were quantified in sequential plasma samples taken over a 25 h period using a targeted LC/MS metabolomics approach. Significant changes with respect to genotype were observed in 89/130 identified metabolites, including sphingolipids, biogenic amines, amino acids and urea. Citrulline and arginine increased significantly in HD compared to control sheep. Ten other amino acids decreased in presymptomatic HD sheep, including branched chain amino acids (isoleucine, leucine and valine) that have been identified previously as potential biomarkers of HD. Significant increases in urea, arginine, citrulline, asymmetric and symmetric dimethylarginine, alongside decreases in sphingolipids, indicate that both the urea cycle and nitric oxide pathways are dysregulated at early stages in HD. Logistic prediction modelling identified a set of 8 biomarkers that can identify 80% of the presymptomatic HD sheep as transgenic, with 90% confidence. This level of sensitivity, using minimally invasive methods, offers novel opportunities for monitoring disease progression in HD patients.
亨廷顿病（HD）患者明显出现恶病质（无法解释的消瘦），这表明代谢失调在 HD 发病机制中起作用，尽管 HD 患者存在代谢异常的证据并不一致。我们对处于无症状期的 HD 转基因和对照绵羊的血浆进行了代谢组学分析。使用靶向 LC/MS 代谢组学方法，在 25 小时的时间内对连续采集的血浆样本进行了代谢物定量分析。与基因型相关的 89/130 种鉴定出的代谢物发生了显著变化，包括鞘脂、生物胺、氨基酸和尿素。与对照组相比，HD 绵羊的瓜氨酸和精氨酸显著增加。10 种其他氨基酸在无症状期 HD 绵羊中减少，包括先前被确定为 HD 潜在生物标志物的支链氨基酸（异亮氨酸、亮氨酸和缬氨酸）。尿素、精氨酸、瓜氨酸、不对称和对称二甲基精氨酸显著增加，鞘脂减少，表明在 HD 早期阶段，尿素循环和一氧化氮途径均失调。逻辑预测模型确定了一组 8 种生物标志物，可以识别 80%的无症状期 HD 绵羊为转基因，置信度为 90%。使用微创方法达到这种灵敏度为监测 HD 患者的疾病进展提供了新的机会。
