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NMR spectroscopy-based metabolomics of Drosophila model of Huntington’s disease suggests altered cell energetics
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2017-09-05 00:00:00 , DOI: 10.1021/acs.jproteome.7b00491
Virender Singh 1 , Raj Kumar Sharma 2 , Thamarailingam Athilingam 1 , Pradip Sinha 1 , Neeraj Sinha 2 , Ashwani Kumar Thakur 1
Affiliation  

Huntington’s disease (HD) is a neurodegenerative disorder induced by aggregation of the pathological form of Huntingtin protein that has expanded polyglutamine (polyQ) repeats. In the Drosophila model, for instance, expression of transgenes with polyQ repeats induce HD-like pathologies progressively correlating with the increasing lengths of these repeats. Previous studies on both animal models and clinical samples have revealed metabolite imbalances during HD progression. To further explore the physiological processes linked to metabolite imbalances during HD, we have investigated 1D 1H NMR spectroscopy-based metabolomics profile of Drosophila HD model. Using multivariate analysis (PCA and PLS-DA) of metabolites obtained from methanolic extracts of fly heads displaying retinal deformations due to polyQ overexpression, we show that the metabolite imbalance during HD are likely to affect cell energetics. Six out of the 35 metabolites analyzed, namely, nicotinamide adenine dinucleotide (NAD), lactate, pyruvate, succinate, sarcosine, and acetoin displayed segregation with progressive severity of HD. Specifically, HD progression was seen associated with reduction in NAD and increase in lactate-to-pyruvate ratio. Further, comparative analysis of fly HD metabolome with those of mouse HD model, and HD human patients, revealed comparable metabolite imbalances suggesting altered cellular energy homeostasis. These findings thus raise the possibility of therapeutic interventions for HD via modulation of cellular energetics.

中文翻译:

基于核磁共振波谱的亨廷顿氏病果蝇模型代谢组学表明细胞能量学改变

亨廷顿舞蹈病(HD)是一种神经退行性疾病,由亨廷顿蛋白的病理形式聚集而引起,这种形式已经扩展了聚谷氨酰胺(polyQ)重复序列。例如,在果蝇模型中,带有polyQ重复序列的转基因表达会诱导与此类重复序列的长度不断增加相关的HD样病理。先前对动物模型和临床样品的研究都表明,HD进展过程中代谢物失衡。为了进一步探讨与高清期间代谢物失衡有关的生理过程,我们研究了基于1D 1 H NMR光谱的果蝇代谢组学概况高清模型。使用多头分析(PCA和PLS-DA)从蝇头的甲醇提取物中获得的代谢物显示由于polyQ过表达而导致的视网膜变形,我们显示HD期间的代谢物失衡可能会影响细胞能量。在所分析的35种代谢产物中,有6种,即烟酰胺腺嘌呤二核苷酸(NAD),乳酸,丙酮酸,琥珀酸,肌氨酸和乙醛显示出分离性,并伴有HD的严重程度。具体而言,可以看到HD进展与NAD的减少和乳酸对丙酮酸比例的增加有关。此外,对蝇HD代谢组与小鼠HD模型和HD人类患者的代谢组进行比较分析,发现可比的代谢物失衡表明细胞能量稳态发生了改变。
更新日期:2017-09-05
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