Comparative Transcriptome Analysis in Monocyte-Derived Macrophages of Asymptomatic GBA Mutation Carriers and Patients with GBA-Associated Parkinson’s Disease

Abstract

Mutations of the GBA gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are the greatest genetic risk factor for Parkinson’s disease (PD) with frequency between 5% and 20% across the world. N370S and L444P are the two most common mutations in the GBA gene. PD carriers of severe mutation L444P in the GBA gene is characterized by the earlier age at onset compared to N370S. Not every carrier of GBA mutations develop PD during one’s lifetime. In the current study we aimed to find common gene expression signatures in PD associated with mutation in the GBA gene (GBA-PD) using RNA-seq. We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested.

Neuroinflammation and Immune Changes in Prodromal Parkinson’s Disease and Other Synucleinopathies

“…Gaucher’s disease iPSC-derived macrophages showed increased pro-inflammatory cytokine expression and lower phagocytosis [ 94 ]. Transcriptome analysis of monocyte-derived macrophages from a small number of controls, manifesting and non-manifesting GBA-PD, showed that pathways related to immune response, development, differentiation, and axonal growth were enriched in the non-manifesting group [ 95 ]. Thaler et al found no differences in blood cytokines between iPD, controls, and manifesting and non-manifesting GBA-PD [ 70 ].…”

Immune Response Modifications in the Genetic Forms of Parkinson’s Disease: What Do We Know?

“…The selective decrease in monocytes is a relevant finding, as they represent a small percentage of total leukocytes and reduced GCase activity in heterogeneous cell populations could be difficult to detect [ 61 ]. Furthermore, comparative transcriptome analysis in monocyte-derived macrophages of four asymptomatic GBA mutation carriers, four controls, and five PD-GBA, revealed in the latter group the deregulation of genes involved in the immune response, mostly related to monocyte and neutrophil chemotaxis, myeloid leukocyte migration, and cellular response to chemokines [ 62 ]. Several studies reported monocyte dysfunction with impaired responsiveness to stimulation as well [ 63 , 64 ].…”

Large-scale proteomics analysis of five brain regions from Parkinson’s disease patients with a GBA1 mutation

“…A number of approaches have been used to attempt to delineate the mechanistic relationship between PD and GBA1 mutations, among them, high throughput omics [9][10][11][12] . Recently we used a unique tissue collection of brain tissues from idiopathic PD (IPD) and PD-GBA patients to perform a non-targeted lipidomics analysis of four different brain regions 13 , namely the striatum (STR), which is part of the nigrostriatal dopaminergic pathway, and also the occipital cortex (OCC), middle temporal gyrus (MTG) and cingulate gyrus (CG).…”