Comprehensive blood metabolomics profiling of Parkinson’s disease reveals coordinated alterations in xanthine metabolism
Authors: de Lope Elisa Gómez , Loo Rebecca Ting Jiin , Rauschenberger Armin , Ali Muhammad , Pavelka Lukas , Marques Tainá M. , Gomes Clarissa P. C. , Krüger Rejko , Glaab Enrico ,   On behalf of the NCER-PD Consortium, Acharya Geeta , Aguayo Gloria , Alexandre Myriam , Ali Muhammad , Ammerlann Wim , Arena Giuseppe , Balling Rudi , Bassis Michele , Batutu Roxane , Beaumont Katy , Becker Regina , Bellora Camille , Berchem Guy , Berg Daniela , Bisdorff Alexandre , Boussaad Ibrahim , Bouvier David , Brockmann Kathrin , Calmes Jessica , Castillo Lorieza , Contesotto Gessica , De Bremaeker Nancy , Diederich Nico , Dondelinger Rene , Ramia Nancy E. , Esteves Daniela , Fagherazzi Guy , Ferrand Jean-Yves , Frauenknecht Katrin , Gantenbein Manon , Gasser Thomas , Gawron Piotr , Ghosh Soumyabrata , Giraitis Marijus , Glaab Enrico , Goergen Martine , De Lope Elisa Gómez , Graas Jérôme , Graziano Mariella , Groues Valentin , Grünewald Anne , Gu Wei , Hammot Gaël , Hanff Anne-Marie , Hansen Linda , Heneka Michael , Henry Estelle , Herbrink Sylvia , Herzinger Sascha , Heymann Michael , Hu Michele , Hundt Alexander , Jacoby Nadine , Lebioda Jacek Jaroslaw , Jarosz Yohan , Jónsdóttir Sonja , Klopfenstein Quentin , Klucken Jochen , Krüger Rejko , Lambert Pauline , Landoulsi Zied , Lentz Roseline , Liepelt Inga , Liszka Robert , Longhino Laura , Lorentz Victoria , Lupu Paula Cristina , Marques Tainá M. , Mackay Clare , Maetzler Walter , Marcus Katrin , Marques Guilherme , Conde Patricia Martins , May Patrick , Mcintyre Deborah , Mediouni Chouaib , Meisch Francoise , Menster Myriam , Minelli Maura , Mittelbronn Michel , Mollenhauer Brit , Mühlschlegel Friedrich , Nati Romain , Nehrbass Ulf , Nickels Sarah , Nicolai Beatrice , Nicolay Jean-Paul , Noor Fozia , Ostaszewski Marek , Gomes Clarissa P. C. , Pachchek Sinthuja , Pauly Claire , Pauly Laure , Pavelka Lukas , Perquin Magali , Lima Rosalina Ramos , Rauschenberger Armin , Rawal Rajesh , Bobbili Dheeraj Reddy , Roomp Kirsten , Rosales Eduardo , Rosety Isabel , Sandt Estelle , Sapienza Stefano , Satagopam Venkata , Schmitt Margaux , Schmitz Sabine , Schneider Reinhard , Schwamborn Jens , Severino Raquel , Sharify Amir , Soboleva Ekaterina , Sokolowska Kate , Thien Hermann , Thiry Elodie , Loo Rebecca Ting Jiin , Trefois Christophe , Trouet Johanna , Tsurkalenko Olena , Vaillant Michel , Valenti Mesele , Van Cutsem Gilles , Vega Carlos , Boas Liliana Vilas , Vyas Maharshi , Wade-Martins Richard , Wilmes Paul , Wollscheid-Lengeling Evi , Zelimkhanov Gelani 
Published: March 2024

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.