Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson’s disease

Abstract

Background Genetic mutations in beta-glucocerebrosidase (GBA) represent the major genetic risk factor for Parkinson’s disease (PD). GBA participates in both the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated. Methods We characterized the transcriptomic profiles of circulating monocytes in a population of patients with PD and healthy controls (CTRL) with and without GBA variants (n = 23 PD/GBA, 13 CTRL/GBA, 56 PD, 66 CTRL) and whole blood (n = 616 PD, 362 CTRL, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy. Results We observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, PD/GBA showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing. Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to non-manifesting GBA-carriers, as also observed at the ultrastructural levels. Transcriptomic results were only partially replicated in an independent cohort of whole blood samples, suggesting cell-type specific changes. Conclusions Overall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.

Development of quantitative high-throughput screening assays to identify, validate, and optimize small-molecule stabilizers of misfolded β-glucocerebrosidase with therapeutic potential for Gaucher disease and Parkinson’s disease

“…In agreement, pharmacological Wnt activation was previously shown to rescue defects in dopaminergic neurogenesis [105] and bone matrix deposition [106] in iPSCs derived from patients with GD. Across the identified molecular targets, the top enriched pathway was NOTCH signaling, which has also been previously linked to GBA1 -PD [107].…”

Free‐Water Imaging of the Substantia Nigra in GBA Pathogenic Variant Carriers

“…It has been demonstrated that non-motor symptoms are commonly presented in GBA-NMC. 10,44 GBA pathogenic variants could increase the risk of developing psychotic symptoms and orthostatic hypotension, [45][46][47] since the pathogenic variants contribute to the dysregulation in genes involved in α-synuclein degradation, aging, and amyloid progressing, 48 and the diffusion of Lewy pathology in the brain and peripheral nervous system in the prodromal stage of PD. 49,50 Free water values in the posterior substantia nigra in the GBA-PD group were higher than those in the GBA-NMC.…”

Who is at Risk of Parkinson Disease? Refining the Preclinical Phase of GBA1 and LRRK2 Variant Carriers: a Clinical, Biochemical, and Imaging Approach

“…Use of analyses such as transcriptomics or proteomics can provide insight into the pathogenic mechanisms implicated in PD development in genetically stratified cohorts; however, their applicability in clinical setting is difficult. For instance, transcriptomic profile of monocytes in a cohort of GBA1-PD, sPD, GBA1-NMC, and HC, did not find any specific gene target or biological process related to GBA1 signature, but gene-based outlier analysis in GBA1-NMC showed involvement of mitochondrial function [70]. When the authors performed the same analysis in an independent and larger cohort of whole blood samples, they only marginally replicated the results suggesting cell-specificity [70].…”

“…For instance, transcriptomic profile of monocytes in a cohort of GBA1-PD, sPD, GBA1-NMC, and HC, did not find any specific gene target or biological process related to GBA1 signature, but gene-based outlier analysis in GBA1-NMC showed involvement of mitochondrial function [70]. When the authors performed the same analysis in an independent and larger cohort of whole blood samples, they only marginally replicated the results suggesting cell-specificity [70]. Another recent study applied unbiased mass-spectrometry phospho-proteomic study in PBMCs to a cohort of LRRK2-G2019S and LRRK2-R1441G carriers (with and without PD).…”