Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232-0252, USA.
Cells. 2021 Mar 5;10(3):572. doi: 10.3390/cells10030572.
Biomarkers currently available for the diagnosis, prognosis, and therapeutic monitoring of GM1 gangliosidosis type 2 (GM1T2) disease are mainly limited to those discovered in targeted proteomic-based studies. In order to identify and establish new, predominantly low-molecular-mass biomarkers for this disorder, we employed an untargeted, multi-analyte approach involving high-resolution H NMR analysis coupled to a range of multivariate analysis and computational intelligence technique (CIT) strategies to explore biomolecular distinctions between blood plasma samples collected from GM1T2 and healthy control (HC) participants ( = 10 and 28, respectively). The relationship of these differences to metabolic mechanisms underlying the pathogenesis of GM1T2 disorder was also investigated. H NMR-linked metabolomics analyses revealed significant GM1T2-mediated dysregulations in ≥13 blood plasma metabolites (corrected < 0.04), and these included significant upregulations in 7 amino acids, and downregulations in lipoprotein-associated triacylglycerols and alanine. Indeed, results acquired demonstrated a profound distinctiveness between the GM1T2 and HC profiles. Additionally, employment of a genome-scale network model of human metabolism provided evidence that perturbations to propanoate, ethanol, amino-sugar, aspartate, seleno-amino acid, glutathione and alanine metabolism, fatty acid biosynthesis, and most especially branched-chain amino acid degradation ( = 10-10) were the most important topologically-highlighted dysregulated pathways contributing towards GM1T2 disease pathology. Quantitative metabolite set enrichment analysis revealed that pathological locations associated with these dysfunctions were in the order fibroblasts > Golgi apparatus > mitochondria > spleen ≈ skeletal muscle ≈ muscle in general. In conclusion, results acquired demonstrated marked metabolic imbalances and alterations to energy demand, which are consistent with GM1T2 disease pathogenesis mechanisms.
目前可用于 GM1 神经节苷脂贮积症 2 型（GM1T2）疾病的诊断、预后和治疗监测的生物标志物主要限于靶向蛋白质组学研究中发现的那些标志物。为了确定和建立新的、主要是低分子量的生物标志物，我们采用了一种非靶向、多分析物方法，涉及高分辨率 H NMR 分析以及一系列多变量分析和计算智能技术（CIT）策略，以探索 GM1T2 疾病患者和健康对照者（分别为 10 人和 28 人）的血浆样本之间的生物分子差异。还研究了这些差异与 GM1T2 疾病发病机制相关的代谢机制之间的关系。H NMR 相关代谢组学分析显示，GM1T2 介导的血液代谢物显著失调（校正后 <0.04），其中包括 7 种氨基酸的显著上调和脂蛋白相关三酰甘油和丙氨酸的下调。实际上，获得的结果表明 GM1T2 和 HC 谱之间存在明显的不同。此外，采用人类代谢的基因组规模网络模型提供了证据，表明丙酸盐、乙醇、氨基糖、天冬氨酸、硒氨基酸、谷胱甘肽和丙氨酸代谢、脂肪酸生物合成以及特别是支链氨基酸降解（= 10-10）的扰动是最重要的拓扑上失调的途径，有助于 GM1T2 疾病的病理。定量代谢物集富集分析显示，与这些功能障碍相关的病变部位的顺序为成纤维细胞>高尔基器>线粒体>脾脏≈骨骼肌≈肌肉。总之，获得的结果表明存在明显的代谢失衡和能量需求改变，这与 GM1T2 疾病发病机制一致。
