Objective: The aim of this case-control study was to examine the association between SNPs located in the promoter region of the RAB7L1 gene and Parkinson’s disease (PD) risk in Russian population, as well as lysosomal hydrolase activity and sphingolipid levels in the blood of PD patients.

Background: Genome-wide association studies have identified RAB7L1 (RAB29) as a significant gene associated with a reduced PD risk. The RAB7L1 protein is a key regulator of the leucine-rich repeat kinase 2 (LRRK2), which plays a crucial role in endolysosomal transport. Previously, we showed that changes in LRRK2 kinase activity correlate with the activity of lysosomal hydrolases in blood of PD patients [1]. We hypothesize that SNPs in the promoter region of RAB7L1, such as rs823144 and rs1572931, may influence RAB7L1 protein function, leading to changes in lysosomal hydrolase transport and contributing to the protective effects against PD.

Method: 543 PD patients and 432 controls were collected for analysis of RAB7L1 rs823144 and rs1572931 polymorphisms by full sequencing of RAB7L1. Activity of lysosomal enzymes (glucocerebrosidase (GCase), alpha-galactosidase A (GLA), acid sphingomyelinase (ASMase) and concentrations of lysosphingolipids (hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), lysosphingomyelin (LysoSM)) were estimated in 211 PD patients and 179 controls by HPLC-MS/MS in dry blood spots.

Results: The RAB7L1 gene C allele of rs823144 and T allele of rs1572931 were associated with a reduced risk of PD in the Russian population (OR: 0.73, 95% CI: 0.59 – 0.91, p=0.005; OR: 0.69, 95% CI: 0.53 – 0.91, p=0.008, respectively), consistent with global data [2]. We assessed for the first time association of studied SNPs with lysosomal hydrolase activities and sphingolipid concentration in blood of PD patients. The C allele of rs823144 was associated with increased GLA activity and decreased LysoGb3 concentration in the blood of PD patients (GLA: β=1.11, p=0.024; LysoGb3: β=-0.23, p=0.015). The T allele of rs1572931 was associated with increased LysoSM concentration in the blood of PD patients (β=4.63, p=0.03).

Conclusion: Our data demonstrate that sequence alterations in the promoter region of RAB7L1 are associated with reduced risk for PD in Russian population. Furthermore, our findings suggest a potential role of RAB7L1gene in sphingolipid metabolism.

References: 1. Usenko, T. S., Senkevich, K. A., Basharova, K. S., Bezrukova, A. I., Baydakova, G. V., Tyurin, A. A., Beletskaya, M. V., Kulabukhova, D. G., Grunina, M. N., Emelyanov, A. K., Miliukhina, I. V., Timofeeva, A. A., Zakharova, E. Y., & Pchelina, S. N. (2023). LRRK2 exonic variants are associated with lysosomal hydrolase activities and lysosphingolipid alterations in Parkinson’s disease. Gene, 882, 147639.
2. Gan-Or Z., Bar-Shira A., Dahary D., Mirelman A., Kedmi M., Gurevich T., Giladi N., Orr-Urtreger A. Association of Sequence Alterations in the Putative Promoter of RAB7L1 With a Reduced Parkinson Disease Risk. Arch Neurol. 2012;69(1):105–110.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-of-sequence-alterations-in-the-promoter-region-of-the-rab7l1-gene-with-lysosomal-hydrolase-activity-in-blood-and-reduced-risk-of-parkinson-disease/