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

Abstract Sex differences significantly influence the pathophysiology of Parkinson’s disease (PD). However, it remains unclear whether sex differences affect blood metabolome profiles in patients with PD-related gene mutations compared to healthy controls (HCs). Here, we conducted a 1 H-Nuclear Magnetic Resonance (NMR) metabolomic analysis of serum samples from a defined cohort of patients carrying variants in LRRK2 (n=17), GBA1 (n=30), PARK2/PINK1/PARK7 (n=40), and TMEM175 (n=32) genes. Their serum metabolomic profiles were compared with those of 48 age- and sex-matched HCs. Additionally, 48 patients with idiopathic PD were included to assess the extent to which metabolomic alterations overlapped between genetically defined and idiopathic PD. Notably, Partial Least Squares Discriminant Analysis indicated significant sexual dimorphism in serum metabolomic profiles between cases and controls across all PD-linked genetic groups. Conversely, multivariate analysis of NMR data did not show clear separation of metabolomic features among patients carrying different pathogenic mutations, nor between genetically defined and idiopathic PD patients. These findings suggest that, despite genetic heterogeneity, PD patients share a common pattern of systemic metabolic alterations. Furthermore, our findings indicate that sex differences significantly influence the blood metabolic profiles of distinct PD-related gene mutations, resulting in unique serum metabolic profiles in mutation carriers compared with matched controls.