Association of the rs823144 variant of the RAB29 gene with the activity of lysosomal hydrolases in blood cells and risk of Parkinson’s disease
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".