Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles
Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles
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DOI：
10.1093/brain/awl027
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发表时间：
2006-04-01
期刊：
影响因子：
14.5
通讯作者：
Rubinsztein, DC
中科院分区：
文献类型：
--
作者：
Underwood, BR;Broadhurst, D;Rubinsztein, DC
最近在开发亨廷顿舞蹈病（HD）的治疗策略方面取得了相当大的进展，几种化合物在转基因小鼠模型中显示出有益的效果。然而，由于疾病病程缓慢、发病隐匿和患者之间的差异，HD的人体试验是困难的、昂贵的和耗时的。识别与疾病进展相关的分子生物标志物将有助于开发有效的治疗方法，允许进一步验证动物模型，并有望提供更敏感的疾病进展测量方法。在这里，我们通过气相色谱-飞行时间质谱法对人类HD患者和转基因小鼠模型的血清样本进行代谢分析，以产生疾病生物标志物的假设。我们观察到转基因小鼠和野生型小鼠的代谢谱存在明显差异，在人类患者和对照组中也有类似的差异趋势。因此，负责区分转基因小鼠的代谢物也包含与人类疾病初步相关的代谢特征。在小鼠和人类中，组成HD相关代谢特征的候选生物标志物表明，在症状出现之前，HD早期的促分解代谢表型发生了变化，脂肪酸分解的各种标志物（包括甘油和丙二酸酯）和某些脂肪族氨基酸也发生了变化。我们的数据提高了在症状出现之前HD进展的强大分子定义的前景，如果以真正前瞻性的方式验证这些生物标志物轨迹，将有助于开发针对该疾病的有用治疗方法。
There has been considerable progress recently towards developing therapeutic strategies for Huntington's disease (HD), with several compounds showing beneficial effects in transgenic mouse models. However, human trials in HD are difficult, costly and time-consuming due to the slow disease course, insidious onset and patient-to-patient variability. Identification of molecular biomarkers associated with disease progression will aid the development of effective therapies by allowing further validation of animal models and by providing hopefully more sensitive measures of disease progression. Here, we apply metabolic profiling by gas chromatography-time-of-flight-mass spectrometry to serum samples from human HD patients and a transgenic mouse model in a hypothesis-generating search for disease biomarkers. We observed clear differences in metabolic profiles between transgenic mice and wild-type littermates, with a trend for similar differences in human patients and control subjects. Thus, the metabolites responsible for distinguishing transgenic mice also comprised a metabolic signature tentatively associated with the human disease. The candidate biomarkers composing this HD-associated metabolic signature in mouse and humans are indicative of a change to a pro-catabolic phenotype in early HD preceding symptom onset, with changes in various markers of fatty acid breakdown (including glycerol and malonate) and also in certain aliphatic amino acids. Our data raise the prospect of a robust molecular definition of progression of HD prior to symptom onset, and if validated in a genuinely prospective fashion these biomarker trajectories could facilitate the development of useful therapies for this disease.