Objective: To identify potential biomarkers of Parkinson’s disease (PD) associated with dysfunction of enzyme glucocerebrosidase (GCase) by a comparative whole transcriptome analysis of animal models and human cells.
Background: Mutations of the GBA gene, encoding the GCase, are the greatest risk factor for PD characterized by the loss of neurons in the substantia nigra (SN). Molecular mechanisms of PD associated with mutations in the GBA gene (GBA-PD) are unknown.
Method: Whole transcriptome analysis was conducted for 16 SN samples of mice divided into groups with following solutions: 0.9 % sodium chloride solution (controls), neurotoxin for mimic PD (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP), inhibitor of GCase (conduritol B epoxide, CBE), MPTP with CBE (MPTP+CBE) and for monocyte-derived-macrophages (MDM) samples of 4 GBA-PD patients, 3 asymptomatic GBA mutation carriers (GBA-carriers) and 4 controls. Comparative study of functional enrichment analysis of identified differentially expressed genes (DEGs) was performed using Gene Ontology (GO). Validation study was conducted in peripheral blood mononuclear cell (PBMC) of 15 GBA-PD patients, 13 GBA-carriers, 17 PD patients and 34 controls by qRT-PCR.
Results: 64 DEGs were identified in SN from mice MPTP vs controls, 23 DEGs in MPTP vs CBE, 20 DEGs in MPTP vs MPTP+CBE, 23 DEGs in MPTP+CBE vs CBE, 37 DEGs in MPTP+CBE vs controls, 2 DEGs in controls vs CBE. 64 DEGs were revealed in MDM from GBA-PD vs controls, 17 DEGs in GBA-carriers vs controls, 85 DEGs in GBA-PD vs GBA-carriers. The combined GO analysis of two datasets revealed alteration in DEGs involved in neurogenesis, apoptosis, autophagy, in particularly, PI3K-Akt-mTOR pathway in MPTP+CBE vs controls, vs MPTP mice and GBA-PD vs controls. Validation analysis of genes (ARL4C, DUSP1, TRIM13, BCL6, ARL4D, PDK4, SGK1) regulated by PI3K-Akt-mTOR shown decreased DUSP1, ARL4С expression and increased ARL4D expression in GBA-PD compared to controls (p<0.05). GBA-PD were characterized by increased ARL4D expression compared to PD and decreased DUSP1 expression than in GBA-carriers (p<0.01).
Conclusion: The alteration in expression profile of genes involved in a key autophagy signaling pathway, PI3K-Akt-mTOR, was revealed. Decreased DUSP1 expression can be considered as a potential biomarker of GBA-PD.
To cite this abstract in AMA style:
A. Bezrukova, K. Basharova, M. Rudenok, M. Nikolaev, A. Kopytova, I. Miliukhina, A. Emelyanov, M. Shadrina, P. Slominsky, S. Pchelina, T. Usenko. Comparative whole transcriptome analysis of human and mice models of Parkinson’s disease bearing defective glucocerebrosidase activity revealed alteration of expression profile of genes involved in the autophagy [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/comparative-whole-transcriptome-analysis-of-human-and-mice-models-of-parkinsons-disease-bearing-defective-glucocerebrosidase-activity-revealed-alteration-of-expression-profile-of-genes-involved-in-t/. Accessed June 15, 2025.« Back to 2023 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/comparative-whole-transcriptome-analysis-of-human-and-mice-models-of-parkinsons-disease-bearing-defective-glucocerebrosidase-activity-revealed-alteration-of-expression-profile-of-genes-involved-in-t/