Association of the rs823144 variant of the RAB29 gene with the activity of lysosomal hydrolases in blood cells and risk of Parkinson’s disease

Recent genome-wide association studies have identified a link between the RAB29 gene and Parkinson's disease (PD). The Rab29 protein encoded by RAB29 regulates leucine-rich repeat kinase 2 (LRRK2). Mutations in the LRRK2 gene increase its kinase activity and contribute to autosomal dominant forms of PD. Previous research has shown that altered LRRK2 kinase activity may correlate with the activity of lysosomal hydrolases and the concentration of sphingolipids. This study aimed to assess the association of the rs823144 variant in the promoter region of the RAB29 gene with PD risk, and to evaluate RAB29 expression, lysosomal hydrolase activity, and sphingolipid concentrations in the blood of PD patients. We screened the rs823144 variant of the RAB29 gene in a cohort of PD patients (N = 903) and controls (N = 618) using next-generation sequencing (NGS) and polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analysis. The expression of the RAB29 gene was measured in peripheral blood mononuclear cells (PBMCs) using qPCR. We assessed the activities of lysosomal hydrolases (glucocerebrosidase (GCase), alpha-galactosidase (GLA), acid sphingomyelinase (ASMase), and galactosylcerebrosidase (GALC)) and the concentrations of sphingolipids (globotriaosylsphingosine (LysoGb3), sphingomyelin (LysoSM), and hexosylsphingosine (HexSph)) in blood using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The RAB29 rs823144 C allele was associated with a reduced risk of PD in the Northwestern Russian population (OR = 0.7806, 95 % CI: 0.6578-0.9263, p = 0.0046), which is consistent with global data. However, no significant association was observed between the rs823144 C allele and RAB29 mRNA expression in PBMCs. Notably, the C allele was associated with increased GLA activity and decreased concentrations of LysoGb3 and LysoSM in the blood of PD patients. In conclusion, we demonstrate for the first time an association between the RAB29 rs823144 C allele and a reduced risk of PD in the Northwestern Russian population. Moreover, the RAB29 rs823144 C allele is associated with altered lysosomal enzyme activity and sphingolipid profiles, suggesting a potential role of RAB29 in sphingolipid metabolism relevant to PD pathogenesis.