Mutations in the GBA1, LRRK2, TMEM175, PARK2, PINK1, and PARK7 genes lead to sex- and genotype-specific serum metabolic changes in patients with Parkinson's disease

IntroductionSex has emerged as a key factor shaping serum metabolomic profiles in idiopathic Parkinsons disease (PD). However, it remains unclear whether sex differences influence circulating metabolic signatures in patients with specific PD-related gene mutations compared to age-matched healthy controls (HCs). MethodsWe conducted an untargeted 1H NMR-based metabolomic analysis of serum in a clinically defined cohort of patients with genetic forms of PD (n = 119) and age- and sex-matched HCs (n = 48). The PD cohort was subdivided into patients carrying LRRK2 (n=17), PARK2/PINK1/PARK7 (n=40), TMEM175 (n=32) or GBA1 (n=30) mutations. ResultsAcross all genotypes, PLS-DA analysis indicated significant differences in serum metabolomes between cases and matched HCs. Pathway enrichment analyses further revealed that PD patients with mutations in LRRK2, PARK2/PINK1/PARK7, TMEM175, or GBA1 showed distinct sex-related metabolic signatures compared with matched controls. Male patients exhibit more pronounced disturbances in amino acid metabolism, whereas females with the same pathogenic mutation show fewer dysregulated pathways, primarily involving lipid-related metabolites. Intriguingly, PLS-DA analysis failed to differentiate the serum metabolomes of patients with different mutations, suggesting a set of metabolic changes reflecting common biochemical abnormalities associated with this neurodegenerative disease. ConclusionOur untargeted NMR-based metabolomic analysis shows that both sex and genotype differences significantly influence the serum metabolome profiles of familial PD patients compared to age-matched healthy controls.