Objective: To study the pathogenic mechanisms associated with mutations of the GBAgenes in Parkinson’s disease (PD).

Background: Mutation of GBA(encoding for glucocerebrosidase, GCase) is one of the major genetic risk factors for PD. However, its role in the pathogenesis of PD has not been fully elucidated. GCase is important in monocytes and macrophages and many recent studies have suggested a central role of the innate immune system in PD. Therefore, an integrative analysis of genomic and transcriptomic. The profiles from monocytes using advanced computational approaches may provide novel insights into the underlying mechanisms of GBAmutation in the pathogenesis of PD.

Method: Blood samples were collected from PD subjects and non-affected subjects with and without a GBAmutation. We used the CD14+ positive isolation kit and the automated machine by Miltenyi to isolate monocytes from peripheral blood mononuclear cells (PBMC). After RNA isolation, Standard protocols were used to prepare ribosomal rRNA depletion libraries. Samples were sequenced at 60M reads per sample with Illumina HiSeq 2500. DNA was extracted and genotyping was performed using Illumina Global Screening Array to generate information on ~700K SNPs. Data from PD-GBA+, PD-GBA-, and CTRLs were compared.

Results: Transcriptomic analysis revealed that monocytes from a pilot cohort of GBA+ PD (n = 10) patients presented specific traits compared to controls (n = 10). In particular, genes involved in mitochondrial functions and inflammation were dysregulated when comparing the different groups. Dysregulation of genes identified in large GWAS-PD studies as well as other previously described genetic risk factors for PD were identified. These results suggested possible interactions between these pathogenic variants as important elements for the pathogenesis of PD in the presence of GBAmutations.

Conclusion: This pilot study suggests a dysregulation of specific pathways in monocytes from GBA-PD patients compared to non-affected subjects that will be suitable for further confirmation in larger cohort of patients. The identification of specific traits in GBAcarriers who develop PD from peripheral blood cells will also offer a promising tool for the identification of suitable disease biomarkers.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/expression-profiles-from-cd14-monocytes-in-pd-patients-with-gba-mutations/