Center for Molecular Biophysics, CBM, UPR 4301, CNRS, Rue Charles SADRON, F-45071 Orléans Cedex 02, France.
University of Orléans, 6 Avenue du Parc Floral, F-45100 Orléans, France.
J Proteome Res. 2020 Oct 2;19(10):4034-4045. doi: 10.1021/acs.jproteome.0c00335. Epub 2020 Sep 22.
Huntington's disease (HD) is an inherited neurodegenerative disorder, for which diagnostic development and discovery of new therapeutic targets are urgently required. In this study, a model of HD in has been used to identify metabolic biomarkers at presymptomatic and symptomatic stages of the disease. The pan-neuronal expression of a pathogenic fragment of the human Huntingtin (HTT) protein containing a 93-repeat polyglutamine expansion (Httex1p Q93) in transgenic flies induces a neuropathology with several characteristics of the human disease. The discriminant metabolites between the diseased flies and their controls were identified by H nuclear magnetic resonance and orthogonal partial least squares discriminant multivariate analysis. The experiments carried out with 10-day-old flies allowed us to identify a set of 10 biomarkers of the presymptomatic stage: NAD, AMP, fumarate, asparagine, dimethylamine, β-alanine, glutamine, succinate, glutamate, and ethanol. Remarkably, the experiments conducted with 16-day-old flies, when the symptoms of the disease were present, highlighted a different set of 6 biomarkers: phosphocholine, ethanolamine, 2-oxoglutarate, succinate, pyruvate, and acetate. Our results provide a better understanding of the metabolic impairments in a widely used HD model and demonstrate that metabolism perturbations change dramatically during the development of the disease.
亨廷顿病（HD）是一种遗传性神经退行性疾病，迫切需要开发诊断方法并发现新的治疗靶点。在本研究中，利用 中的 HD 模型来鉴定疾病的无症状和有症状阶段的代谢生物标志物。在转基因果蝇中，人类 Huntingtin（HTT）蛋白的致病性片段（含有 93 个重复的聚谷氨酰胺扩展）的全神经元表达诱导出具有人类疾病多种特征的神经病理学。通过 H 核磁共振和正交偏最小二乘判别多元分析鉴定出患病果蝇与其对照之间的差异代谢物。用 10 日龄的果蝇进行的实验使我们能够鉴定出一组 10 种无症状阶段的生物标志物：NAD、AMP、延胡索酸、天冬酰胺、二甲胺、β-丙氨酸、谷氨酰胺、琥珀酸、谷氨酸和乙醇。值得注意的是，用 16 日龄的果蝇进行的实验，当疾病出现症状时，突出了一组不同的 6 种生物标志物：磷酸胆碱、乙醇胺、2-氧戊二酸、琥珀酸、丙酮酸和乙酸。我们的研究结果提供了对广泛使用的 HD 模型中代谢损伤的更好理解，并表明代谢紊乱在疾病发展过程中发生了巨大变化。
