Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina 188300, Russia.
Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg 197022, Russia.
Genes (Basel). 2021 Sep 29;12(10):1545. doi: 10.3390/genes12101545.
Mutations of the 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 gene. PD carriers of severe mutation L444P in the gene is characterized by the earlier age at onset compared to N370S. Not every carrier of 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 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 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 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 in the pathogenesis of GBA-PD was suggested.
基因的突变，编码溶酶体酶葡萄糖脑苷脂酶（GCase），是帕金森病（PD）最大的遗传风险因素，在全球范围内频率为 5%至 20%。N370S 和 L444P 是 基因中最常见的两种突变。携带严重突变 L444P 的 PD 患者的发病年龄早于 N370S。并非每个携带 基因突变的患者在其一生中都会发展为 PD。在本研究中，我们旨在使用 RNA-seq 寻找与 基因（GBA-PD）突变相关的 PD 常见基因表达特征。我们比较了 5 名 GBA-PD（4 名 L444P/N，1 名 N370S/N）和 4 名无症状 基因突变携带者（GBA-携带者）（3 名 L444P/N，1 名 N370S/N）和 4 名对照者的单核细胞来源的巨噬细胞转录组。我们还对仅 L444P/N 的 GBA-PD 患者和 GBA-携带者进行了比较转录组分析。在 GBA-PD 中独立于突变（L444P 或 N370S）下调的基因参与免疫反应、神经元功能。我们发现 L444P/N GBA-PD 患者中与锌代谢相关的上调途径。提示 基因在 GBA-PD 发病机制中可能具有重要作用。
