Anna C Pfalzer, Shuhei Shiino, James Silverman, Simona G Codreanu, Stacy D Sherrod, John A McLean, Daniel O Claassen
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引用次数: 0
Abstract
Background: Huntington's disease (HD) is a neurodegenerative disorder caused by expanded cytosine-adenine-guanine (CAG) repeats in the Huntingtin gene, resulting in the production of mutant huntingtin proteins (mHTT). Previous research has identified urea as a key metabolite elevated in HD animal models and postmortem tissues of HD patients. However, the relationship between disease course and urea elevations, along with the molecular mechanisms responsible for these disturbances remain unknown.
Objective: To better understand the molecular disturbances and timing of urea cycle metabolism across different stages in HD.
Methods: We completed a global metabolomic profile of cerebrospinal fluid (CSF) from individuals who were at several stages of disease: pre-manifest (PRE), manifest (MAN), and late manifest (LATE) HD participants, and compared to controls.
Results: Approximately 500 metabolites were significantly altered in PRE participants compared to controls, although no significant differences in CSF urea or urea metabolites were observed. CSF urea was significantly elevated in LATE participants only. There were no changes in the urea metabolites citrulline, ornithine, and arginine.
Conclusions: Overall, our study confirms that CSF elevations occur late in the HD course, and these changes may reflect accumulating deficits in cellular energy metabolism.
背景:亨廷顿氏病(Huntington's disease,HD)是一种神经退行性疾病,由亨廷廷基因中的胞嘧啶-腺嘌呤-鸟嘌呤(CAG)重复序列扩增导致突变亨廷廷蛋白(mHTT)的产生。先前的研究发现,尿素是 HD 动物模型和 HD 患者死后组织中升高的一种关键代谢物。然而,病程与尿素升高之间的关系以及导致这些紊乱的分子机制仍不清楚:目的:更好地了解 HD 不同阶段尿素循环代谢的分子干扰和时间:我们对处于不同病程阶段的 HD 患者的脑脊液(CSF)进行了全面的代谢组学分析:显现前(PRE)、显现期(MAN)和显现晚期(LATE),并与对照组进行了比较:结果:与对照组相比,PRE 患者体内约有 500 种代谢物发生了明显变化,但 CSF 尿素或尿素代谢物没有发现明显差异。只有晚期患者的脑脊液尿素明显升高。尿素代谢物瓜氨酸、鸟氨酸和精氨酸没有变化:总之,我们的研究证实了 CSF 升高发生在 HD 病程的晚期,这些变化可能反映了细胞能量代谢的累积性缺陷。