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 Becker, Camille Bellora, Guy Berchem, Daniela Berg, Alexandre Bisdorff, Ibrahim Boussaad, David Bouvier, Kathrin Brockmann, Jessica Calmes, Lorieza Castillo, Gessica Contesotto, Nancy De Bremaeker, Nico J. 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 Grouès, Anne Grünewald, Wei Gu, Gaël Hammot, Anne-Marie Hanff, Linda Hansen, Michael T. Heneka, Estelle Henry, Sylvia Herbrink, Sascha Herzinger, Michaël 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 E. Mackay, Walter Maetzler, Katrin Marcus, Guilherme Fernandes Marques, Patricia Martins Conde, Patrick May, Deborah McIntyre, Chouaib Mediouni, Françoise Meisch, Myriam Menster, Maura Minelli, Michel Mittelbronn, Brit Mollenhauer, Friedrich Mühlschlegel, Romain Nati, Ulf Nehrbass, Sarah Nickels, Béatrice Nicolai, Jean-Paul Nicolay, Fozia Noor, Marek Ostaszewski, Clarissa P. C. Gomes, Sinthuja Pachchek
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.