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

Parkinson's disease (PD) is a highly heterogeneous disorder with several environmental and genetic factors contributing to the disease initiation and progression. Effective disease-modifying therapies and robust biomarker signatures for the early pre-motor and motor stages of the disease are still lacking, and an improved understanding of the molecular changes characterizing PD could help to reveal new diagnostic and prognostic markers and possible targets for the study of pharmaceutical interventions.
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.