Weinstock Nadav I, Wrabetz Lawrence, Feltri M Laura, Shin Daesung
Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
J Neurosci Res. 2016 Nov;94(11):1094-107. doi: 10.1002/jnr.23789.
Krabbe disease (KD) is caused by mutations in the galactosylceramidase (GALC) gene, which encodes a lysosomal enzyme that degrades galactolipids, including galactosylceramide and galactosylsphingosine (psychosine). GALC deficiency results in progressive intracellular accumulation of psychosine, which is believed to be the main cause for the demyelinating neurodegeneration in KD pathology. Umbilical cord blood transplantation slows disease progression when performed presymptomatically but carries a significant risk of morbidity and mortality. Accurate presymptomatic diagnosis is therefore critical to facilitate the efficacy of existing transplant approaches and to avoid unnecessary treatment of children who will not develop KD. Unfortunately, current diagnostic criteria, including GALC activity, genetic analysis, and psychosine measurement, are insufficient for secure presymptomatic diagnosis. This study performs a global metabolomic analysis to identify pathogenetic metabolic pathways and novel biomarkers implicated in the authentic mouse model of KD known as twitcher. At a time point before onset of signs of disease, twitcher hindbrains had metabolic profiles similar to WT, with the exception of a decrease in metabolites related to glucose energy metabolism. Many metabolic pathways were altered after early signs of disease in the twitcher, including decreased phospholipid turnover, restricted mitochondrial metabolism of branched-chain amino acids, increased inflammation, and changes in neurotransmitter metabolism and osmolytes. Hypoxanthine, a purine derivative, is increased before signs of disease appear, suggesting its potential as a biomarker for early diagnosis of KD. Additionally, given the early changes in glucose metabolism in the pathogenesis of KD, diagnostic modalities that report metabolic function, such as positron emission tomography, may be useful in KD. © 2016 Wiley Periodicals, Inc.
克拉伯病（KD）由半乳糖神经酰胺酶（GALC）基因突变引起，该基因编码一种溶酶体酶，可降解半乳糖脂，包括半乳糖神经酰胺和半乳糖鞘氨醇（psychosine）。GALC缺乏导致psychosine在细胞内进行性蓄积，这被认为是KD病理过程中脱髓鞘神经变性的主要原因。症状前进行脐带血移植可减缓疾病进展，但有显著的发病和死亡风险。因此，准确的症状前诊断对于提高现有移植方法的疗效以及避免对不会患KD的儿童进行不必要的治疗至关重要。不幸的是，目前的诊断标准，包括GALC活性、基因分析和psychosine测量，不足以进行可靠的症状前诊断。本研究进行了一项全面的代谢组学分析，以确定在称为抽搐小鼠的KD真实小鼠模型中涉及的致病代谢途径和新型生物标志物。在疾病迹象出现前的一个时间点，抽搐小鼠的后脑代谢谱与野生型相似，但与葡萄糖能量代谢相关的代谢物有所减少。抽搐小鼠出现疾病早期迹象后，许多代谢途径发生了改变，包括磷脂周转减少、支链氨基酸的线粒体代谢受限、炎症增加以及神经递质代谢和渗透溶质的变化。次黄嘌呤，一种嘌呤衍生物，在疾病迹象出现前增加，表明其作为KD早期诊断生物标志物的潜力。此外，鉴于KD发病机制中葡萄糖代谢的早期变化，报告代谢功能的诊断方法，如正电子发射断层扫描，可能对KD有用。© 2016威利期刊公司
