Plasma metabolic profile delineates roles for neurodegeneration, pro-inflammatory damage and mitochondrial dysfunction in the FMR1 premutation
Plasma metabolic profile delineates roles for neurodegeneration, pro-inflammatory damage and mitochondrial dysfunction in the FMR1 premutation
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DOI：
10.1042/bcj20160585
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发表时间：
2016-11-01
影响因子：
4.1
通讯作者：
Hagerman, Randi
中科院分区：
文献类型：
--
作者：
Giulivi, Cecilia;Napoli, Eleonora;Hagerman, Randi
脆性X智力发育迟滞1 （FMR1）基因突变前CGG扩增的携带者发生迟发性神经退行性疾病的风险更高，称为脆性X相关震颤共济失调综合征（FXTAS）。鉴于线粒体功能障碍已经在成纤维细胞、PBMC和来自携带者的大脑样本以及预突变动物模型中被发现，线粒体处于中间代谢的中心，本研究的目的是通过揭示预突变携带者的血浆代谢扰动，提供一个完整的代谢模式。为此，对23名突变前个体和16名年龄和性别匹配的对照组的血浆代谢谱进行了评估。在受影响的途径中，线粒体功能障碍与warburg样移位相关，乳酸水平升高，克雷布斯中间体、神经递质、神经变性标志物改变，氧化应激介导的生物分子损伤增加。CGG重复序列的数量与血浆代谢物的一个子集相关，这不仅与线粒体疾病有关，而且与其他神经系统疾病有关，如帕金森病、阿尔茨海默病和亨廷顿病。这是第一次，确定的途径揭示了导致前突变发病率的疾病机制，具有在纵向研究中评估代谢物作为发病率或疾病进展指标的潜力，特别是在早期临床前阶段。
Carriers of premutation CGG expansions in the fragile X mental retardation 1 (FMR1) gene are at higher risk of developing a late-onset neurodegenerative disorder named Fragile X-associated tremor ataxia syndrome (FXTAS). Given that mitochondrial dysfunction has been identified in fibroblasts, PBMC and brain samples from carriers as well as in animal models of the premutation and that mitochondria are at the center of intermediary metabolism, the aim of the present study was to provide a complete view of the metabolic pattern by uncovering plasma metabolic perturbations in premutation carriers. To this end, metabolic profiles were evaluated in plasma from 23 premutation individuals and 16 age- and sex-matched controls. Among the affected pathways, mitochondrial dysfunction was associated with a Warburg-like shift with increases in lactate levels and altered Krebs' intermediates, neurotransmitters, markers of neurodegeneration and increases in oxidative stress-mediated damage to biomolecules. The number of CGG repeats correlated with a subset of plasma metabolites, which are implicated not only in mitochondrial disorders but also in other neurological diseases, such as Parkinson's, Alzheimer's and Huntington's diseases. For the first time, the identified pathways shed light on disease mechanisms contributing to morbidity of the premutation, with the potential of assessing metabolites in longitudinal studies as indicators of morbidity or disease progression, especially at the early preclinical stages.