Comprehensive blood metabolomics profiling of Parkinson’s disease reveals coordinated alterations in xanthine metabolism

Elisa Gómez de Lope, Rebecca Ting Jiin Loo, Armin Rauschenberger, Muhammad Ali, Lukas Pavelka, Tainá M. Marques, Clarissa P.C. Gomes, Rejko Krüger, Enrico Glaab*, Geeta Acharya, Gloria Aguayo, Myriam Alexandre, Muhammad Ali, Wim Ammerlann, Giuseppe Arena, Rudi Balling, Michele Bassis, Roxane Batutu, Katy Beaumont, Regina BeckerCamille Bellora, Guy Berchem, Daniela Berg, Alexandre Bisdorff, Ibrahim Boussaad, David Bouvier, Kathrin Brockmann, Jessica Calmes, Lorieza Castillo, Gessica Contesotto, Nancy De Bremaeker, Nico Diederich, Rene Dondelinger, Nancy E. Ramia, Daniela Esteves, Guy Fagherazzi, Jean Yves Ferrand, Katrin Frauenknecht, Manon Gantenbein, Thomas Gasser, Piotr Gawron, Soumyabrata Ghosh, Marijus Giraitis, Enrico Glaab*, Martine Goergen, Elisa Gómez De Lope, Jérôme Graas, Mariella Graziano, Valentin Groues, Anne Grünewald, Wei Gu, Gaël Hammot, Anne Marie Hanff, Linda Hansen, Michael Heneka, Estelle Henry, Sylvia Herbrink, Sascha Herzinger, Michael Heymann, Michele Hu, Alexander Hundt, Nadine Jacoby, Jacek Jaroslaw Lebioda, Yohan Jarosz, Sonja Jónsdóttir, Quentin Klopfenstein, Jochen Klucken, Rejko Krüger, Pauline Lambert, Zied Landoulsi, Roseline Lentz, Inga Liepelt, Robert Liszka, Laura Longhino, Victoria Lorentz, Paula Cristina Lupu, Tainá M. Marques, Clare Mackay, Walter Maetzler, Katrin Marcus, Guilherme Marques, Patricia Martins Conde, Patrick May, Deborah Mcintyre, Chouaib Mediouni, Francoise Meisch, Myriam Menster, Maura Minelli, Michel Mittelbronn, Brit Mollenhauer, Friedrich Mühlschlegel, Romain Nati, Ulf Nehrbass, Sarah Nickels, Beatrice Nicolai, Jean Paul Nicolay, Fozia Noor, Marek Ostaszewski, Clarissa P.C. Gomes, Sinthuja Pachchek, Claire Pauly, Laure Pauly, Lukas Pavelka, Magali Perquin, Rosalina Ramos Lima, Armin Rauschenberger, Rajesh Rawal, Dheeraj Reddy Bobbili, Kirsten Roomp, Eduardo Rosales, Isabel Rosety, Estelle Sandt, Stefano Sapienza, Venkata Satagopam, Margaux Schmitt, Sabine Schmitz, Reinhard Schneider, Jens Schwamborn, Raquel Severino, Amir Sharify, Ekaterina Soboleva, Kate Sokolowska, Hermann Thien, Elodie Thiry, Rebecca Ting Jiin Loo, Christophe Trefois, Johanna Trouet, Olena Tsurkalenko, Michel Vaillant, Mesele Valenti, Gilles Van Cutsem, Carlos Vega, Liliana Vilas Boas, Maharshi Vyas, Richard Wade-Martins, Paul Wilmes, Evi Wollscheid-Lengeling, Gelani Zelimkhanov

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Parkinson’s disease (PD) is a highly heterogeneous disorder influenced by several environmental and genetic factors. Effective disease-modifying therapies and robust early-stage biomarkers are still lacking, and an improved understanding of the molecular changes in PD could help to reveal new diagnostic markers and pharmaceutical targets. Here, we report results from a cohort-wide blood plasma metabolic profiling of PD patients and controls in the Luxembourg Parkinson’s Study to detect disease-associated alterations at the level of systemic cellular process and network alterations. We identified statistically significant changes in both individual metabolite levels and global pathway activities in PD vs. controls and significant correlations with motor impairment scores. As a primary observation when investigating shared molecular sub-network alterations, we detect pronounced and coordinated increased metabolite abundances in xanthine metabolism in de novo patients, which are consistent with previous PD case/control transcriptomics data from an independent cohort in terms of known enzyme-metabolite network relationships. From the integrated metabolomics and transcriptomics network analysis, the enzyme hypoxanthine phosphoribosyltransferase 1 (HPRT1) is determined as a potential key regulator controlling the shared changes in xanthine metabolism and linking them to a mechanism that may contribute to pathological loss of cellular adenosine triphosphate (ATP) in PD. Overall, the investigations revealed significant PD-associated metabolome alterations, including pronounced changes in xanthine metabolism that are mechanistically congruent with alterations observed in independent transcriptomics data. The enzyme HPRT1 may merit further investigation as a main regulator of these network alterations and as a potential therapeutic target to address downstream molecular pathology in PD.

Original languageEnglish
Article number68
Journalnpj Parkinson's Disease
Volume10
Issue number1
DOIs
Publication statusPublished - 19 Mar 2024

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