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

• Applicant: Dr. Alexander Balck
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438479242

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.

• DFG Programme: Research Fellowships
• International Connection: Netherlands
• Host: Professor Dr. Thomas Hankemeier