Leiden University Scholarly Publications

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Huang, L. (2024)

Metabolomics assisted with stable-isotope labeling: exploring neuronal metabolism related to Parkinson’s disease

Doctoral Thesis
The progressive loss and degeneration of dopaminergic neurons is a major pathological hallmark of Parkinson's disease (PD). The onset and progression of PD can be triggered by multiple risk factors, for instance, genetic mutation, environmental exposure, and aging. Each factor may cause common or unique metabolic disturbances, ultimately converging into a complex metabolic disorder with diverse clinical phenotypes. Through metabolome analysis, the full picture of the metabolic landscape depicting a biological system can be revealed. Metabolites function as key elements and direct read-outs of a system’s functional status. Alterations in metabolite concentrations are informative for inferring and understanding underlying metabolic activity. In addition, stable isotope labeling techniques coupled with metabolomics can bring us an extra-dynamic vision of the metabolic landscape. Changes in labeling patterns of metabolites help identify alterations with metabolic fluxes through...Show moreThe progressive loss and degeneration of dopaminergic neurons is a major pathological hallmark of Parkinson's disease (PD). The onset and progression of PD can be triggered by multiple risk factors, for instance, genetic mutation, environmental exposure, and aging. Each factor may cause common or unique metabolic disturbances, ultimately converging into a complex metabolic disorder with diverse clinical phenotypes. Through metabolome analysis, the full picture of the metabolic landscape depicting a biological system can be revealed. Metabolites function as key elements and direct read-outs of a system’s functional status. Alterations in metabolite concentrations are informative for inferring and understanding underlying metabolic activity. In addition, stable isotope labeling techniques coupled with metabolomics can bring us an extra-dynamic vision of the metabolic landscape. Changes in labeling patterns of metabolites help identify alterations with metabolic fluxes through pathways. This thesis aimed to develop a comprehensive analytical strategy for characterizing the metabolic activity related to PD neurodegeneration, especially focused on the improvement in metabolome coverage and data quality, facilitating the use of stable isotope labeling in in-depth metabolism investigations, and developing a computational workflow for metabolic flux analysis. These methods were applied to investigate metabolic dysregulation of dopaminergic neurons due to genetic and environmental factors.Show less
Metabolomics
Hydrophilic interaction chromatography
High-resolution LC-MS
Stable-isotope labeling
Metabolic flux analysis
Metabolite moiety isotopologues
Progressive neurodegeneration
Genome-scale flux analysis
Mitochondrial dysfunction
Glutathione metabolism
All authors
Huang, L.
Supervisor
Hankemeier, T.
Co-supervisor
Wegrzyn, A.B.; Fleming, R.M.
Committee
Irth, H.; Lange, E.C.M. de; Aerts, J.M.F.G.; Bakker, B.M.; Cascante, M.
Qualification
Doctor (dr.)
Awarding Institution
Leiden Academic Centre for Drug Research (LACDR), Faculty of Science, Leiden University
Date
2024-01-25
ISBN (print)
9789493289383