Characterization of metabolomic biomarkers from a clinical study with coenzyme Q10 in genetically stratified Parkinson’s disease patients

目前，临床上已明确确定了6个帕金森病（PD）的基因，其中包括3个常染色体reckoning遗传的基因（Parkin，PINK 1，DJ-1）。Parkin和PINK 1编码参与线粒体质量控制及其调节的蛋白质，包括有丝分裂、线粒体自噬和线粒体稳态和转运等过程。因此，线粒体功能障碍在PD的病理中起着关键作用，这一点已被广泛接受。代谢组学是对生物材料样品中大量代谢物的定量测量，然后进行生物信息学分析。代谢酶参与了大量的生化作用，如表观遗传机制，调节翻译后机制，并启动信号级联。预测疾病、测量进展或监测治疗的代谢组学生物标志物可能是单个分子，也可能是几个分子的模式。基于遗传学和生物标志物将PD分为不同的亚组是非常及时的，因为第一个基因特异性治疗正在开发中。我们目前正在进行一项名为“MitoPD”的双盲、随机、安慰剂对照临床试验，研究泛醌治疗的有益效果，泛醌是一种线粒体增强剂。研究参与者是PD患者，根据线粒体功能障碍的预期程度分为四个亚组。具有最显著预期功能障碍的亚组包括在Parkin或PINK 1基因中具有双等位基因突变的PD患者。线粒体功能受损的IPD患者将使用创新的“组学”方法进行识别。拟议的项目将在泛醌干预试验期间纵向研究MitoPD参与者的代谢组。将在治疗前、治疗期间和治疗后采集血液和尿液。在运送到莱顿大学后，将分析生物材料的氨基酸、谷胱甘肽、生物胺、儿茶酚胺和氧化应激标志物，包括异前列烷、亚硝化应激标志物、溶血磷脂、胆汁酸、氧脂、异丙肾上腺素、内源性大麻素、鞘氨醇、二氢鞘氨醇、我们的目标是i）在两种不同的生物材料中定义四组的候选代谢组学特征，以及ii）在IPD、Parkin-和PINK 1-PD患者中检查辅酶Q10治疗在四个时间点的效果。我们假设未经治疗的线粒体功能障碍患者（Parkin-和PINK 1-PD患者和被归类为“Mito-PD”的IPD患者）的原始代谢组学特征将由于辅酶Q10治疗而改变。总之，我们的目标是发现在特定形式的PD中改变的代谢组学途径，并且可以通过泛醌治疗来恢复。这些途径也可能被用作未来的生物标志物。

At present, six genes have been unequivocally established for the clinically classical form of Parkinson’s disease (PD), including three autosomal recessively inherited ones (Parkin, PINK1, DJ-1). Parkin and PINK1 encode proteins that are involved in mitochondrial quality control and its regulation, including processes such as mitogenesis, mitophagy, and mitochondrial homeostasis and transport. It is thus widely accepted that mitochondrial dysfunction plays a pivotal role in the pathology of PD.Metabolomics is the quantitative measurement of a large number of metabolites within a sample of biomaterials, followed by bioinformatics analysis. Metabolites are involved in a plethora of biochemical actions, such as epigenetic mechanisms, regulate post-translational mechanisms, and initiate signaling cascades. A metabolomic biomarker that predicts disease, measures progression, or monitors therapy could potentially be a single molecule, as well as a pattern of several molecules.Stratifying PD into different subgroups based on genetics and biomarkers is very timely because first gene-specific therapies are being developed. We are currently conducting a double-blinded, randomized, placebo-controlled clinical trial called "MitoPD" that investigates the beneficial effects of ubiquinone treatment, which is a mitochondrial enhancer. Study participants are PD patients that are divided into four subgroups according to the expected degree of mitochondrial dysfunction. The subgroups with the most significant expected dysfunction include PD patients with biallelic mutations in the Parkin or PINK1 genes. IPD patients with impaired mitochondrial function will be identified using an innovative "omics" approach.The proposed project will longitudinally investigate the metabolome of the MitoPD participants during the interventional trial with ubiquinone. Blood and urine will be obtained prior, during, and after treatment. After shipment to Leiden University, the biomaterials will be analyzed regarding amino acids, glutathione, biogenic amines, catecholamines, and oxidative stress markers including isoprostanes, nitrosative stress markers, lysophospholipids, bile acids, oxylipins, prostaglandins, endocannabinoids, sphingosine, sphinganine, and fatty acids.We aim to i) define a candidate metabolomic signature of the four groups in two different biomaterials and ii) examine the effects of coenzyme Q10 treatment at four time points in IPD, Parkin- and PINK1-PD patients. We hypnotize that the original metabolomic signature of untreated patients with mitochondrial dysfunction (Parkin- and PINK1-PD patients and IPD patients classified as "Mito-PD") will change due to treatment with coenzyme Q10.In conclusion, we aim to discover metabolomic pathways that are altered in specific forms of PD and can be restored by ubiquinone treatment. Potentially, these pathways may also be used as future biomarkers.