System-wide profiling reveals metabolic alterations in a G2019S LRRK2 knockin mouse model of Parkinson's disease: systemic depletion of pyrimidine nucleosides

BackgroundThe G2019S mutation in LRRK2 is the most common genetic cause of familial Parkinsons disease (PD) and is associated with increased susceptibility to sporadic PD, which likely arises from the interplay of genetic predisposition, environmental exposure, and aging. Metabolic syndrome (MetS) has been implicated as an independent risk factor for PD, but the potential interaction between the G2019S LRRK2 mutation and metabolic stress in disease pathogenesis remains unclear. MethodsWe employed long-term high-fat diet (HFD) feeding to induce metabolic syndrome in aged LRRK2 mutant mice, followed by system-wide characterization using multi-omic approaches, including metabolomic profiling, proteomics, bulk RNA sequencing, and single-nucleus RNA sequencing. ResultsWe find that thymidine and deoxyuridine levels are consistently reduced across tissues in G2019S LRRK2 knockin mice at baseline, accompanied by increased hepatic expression of thymidine phosphorylase (TP). HFD exposure further unmasks disruptions in purine and energy metabolism in the brain and lungs of G2019S LRRK2 knockin mice, with astrocytes and oligodendrocytes in the ventral midbrain exhibiting the most pronounced impairment in oxidative phosphorylation transcriptional pathways. ConclusionsOur findings demonstrate that pre-existing metabolic syndrome unmasks widespread disruptions in systemic nucleotide and energy metabolism and exacerbates mitochondrial dysfunction in G2019S LRRK2 knockin mice. This conditional "two-hit" phenotype underscores the critical role of environmental factors, such as diet, in revealing metabolic vulnerabilities associated with PD-linked genetic backgrounds. Our study provides novel insight into potential metabolic targets or pathways for therapeutic intervention in individuals at-risk for developing PD.