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

Tatiana Usenko,Irina Miliukhina,Sofya Pchelina,Ekaterina Zakharova,Katerina Basharova,Alena Kopytova,Anastasia Bezrukova,Alexandra Panteleeva,Mikhail Nikolaev,Anton Emelyanov

doi:10.3390/genes12101545

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.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by the accumulation of abnormal protein aggregates of alpha-synuclein in the brain [1,2]
A whole-transcriptome analysis of monocyte-derived macrophages obtained from four patients with L444P/N GBA-PD, three L444P/N GBA carriers, and controls without any GBA mutations (N = 4) was performed
Transcriptome analysis of monocyte-derived macrophages was conducted for all GBA-PD patients (L444P/N, N = 4, N370S/N, N = 1), and GBA carriers (L444P/N, N = 3, N370S/N, N = 1)

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by the accumulation of abnormal protein aggregates of alpha-synuclein in the brain [1,2]. Several genetic factors have been associated with an increased risk of PD development. Mutations in the GBA gene are the highest genetic risk factors for PD with an increase of PD risk (of seven to eight times) and with a frequency of 5% to 20% in all populations [3,4]. The GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), is the key enzyme in ceramide metabolism and catalyzes the hydrolysis of glucosylceramide to glucose and ceramide. GBA mutations resulted in the most common lysosomal storage disorder (LSD), Gaucher disease (GD), characterized with lysosphingolipid accumulation, presumably in blood macrophages

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