Objective: To identify modifiers of Parkinson’s disease (PD) among carriers of mutations in the GBA1 gene based on transcriptome data validation analysis by the assessing the expression profile of the PI3K/AKT/mTOR pathway in peripheral blood mononuclear cells.
Background: Mutations in the lysosomal enzyme glucocerebrosidase beta (GCase) (GBA1) gene are the most common of the currently known PD genetic mutations (GBA1-PD) However, not all GBA1 mutation carriers (GBA1-Carriers) develop PD during their lifetime. Previously, we identified alterations in the gene expression profile of the PI3K/AKT/mTOR signaling pathway in cellular and animal models of parkinsonism with GCase dysfunction compared to cellular and animal models with GCase dysfunction alone using transcriptome analysis [1,2].
Method: For validation analysis, genes were selected based on our previous transcriptome studies of cellular and animal models of parkinsonism with GCase dysfunction. A total of 12 genes (DUSP1, ARL4C, IL6, NR4A2, BCL6, EGR1, TRIM13, SGK1, PDK4, ARL4D, DDIT4, MEF2C) were chosen. Expression levels of selected genes were assessed in peripheral blood mononuclear cells of 17 patients with GBA1-PD and 17 GBA1-carriers using qPCR-RT.
Results: During validation, we focused on genes with differential expression between GBA1-PD and GBA1-carriersas they may represent potential PD modifiers among GBA1 mutation carriers. Among the 12 genes analyzed only 4 genes demonstrated statistically significant reduced expression (DUSP1, ARL4C, NR4A2, DDIT4) in GBA1-PD patients compared to GBA1-carriers (p<0.05). To assess the predictive ability of these differences in gene expression levels, ROC analysis was performed. According to the obtained results, PD status in GBA1 mutations carriers could be identified on gene expression levels of the DUSP1, ARL4C, NR4A2, DDIT4 genes below 1.67 (AUC=0.992, p<0.001), 3.63 (AUC=0.821, p=0.01), 1.22 (AUC=0.847, p=0.003), 0.73 (AUC=0.760, p=0.003), respectively.
Conclusion: Our study demonstrates that alteration in the gene expression profile of the PI3K/AKT/mTOR pathway occur in GBA1 mutation carriers. Alterations in DUSP1, ARL4C, NR4A2, DDIT4 expression levels may be considered as potential modifier of PD among GBA1 mutations carriers. which These findings could facilitate early diagnosis of the disease.
Study was supported by Russian Science Foundation grant No. 24-25-00212
References: 1. Usenko T, Bezrukova A, Basharova K, Panteleeva A, Nikolaev M, Kopytova A, Miliukhina I, Emelyanov A, Zakharova E, Pchelina S. Comparative Transcriptome Analysis in Monocyte-Derived Macrophages of Asymptomatic GBA Mutation Carriers and Patients with GBA-Associated Parkinson’s Disease. Genes (Basel). 2021 Sep 29;12(10):1545. doi: 10.3390/genes12101545.
2. Usenko T, Bezrukova A, Rudenok MM, Basharova K, Shadrina MI, Slominsky PA, Zakharova E, Pchelina S. Whole Transcriptome Analysis of Substantia Nigra in Mice with MPTP-Induced Parkinsonism Bearing Defective Glucocerebrosidase Activity. Int J Mol Sci. 2023 Jul 29;24(15):12164. doi: 10.3390/ijms241512164.
To cite this abstract in AMA style:
A. Bezrukova, K. Basharova, I. Miliukhina, S. Pchelina, T. Usenko. Modifiers of Parkinson’s disease associated with mutations in the GBA1 gene based on transcriptome data validation [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/modifiers-of-parkinsons-disease-associated-with-mutations-in-the-gba1-gene-based-on-transcriptome-data-validation/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/modifiers-of-parkinsons-disease-associated-with-mutations-in-the-gba1-gene-based-on-transcriptome-data-validation/