The Marlene and Paolo Fresco Institute for Parkinson's Disease and Movement Disorders, New York University Langone Health, 222 East 41st street, New York, NY, 10017, USA.
Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Mol Neurodegener. 2022 Aug 17;17(1):52. doi: 10.1186/s13024-022-00554-8.
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.
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.
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.
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.
β-葡糖苷脑苷脂酶 (GBA) 的基因突变是帕金森病 (PD) 的主要遗传风险因素。GBA 参与内溶酶体途径和免疫反应，这是 PD 发病机制中两个重要的机制。然而，GBA 外显率的修饰因子尚未完全阐明。
我们对携带 GBA 变异的 PD 患者和健康对照者（CTRL）的循环单核细胞的转录组谱进行了特征描述（n=23 PD/GBA、13 CTRL/GBA、56 PD、66 CTRL），并进行了全血（n=616 PD、362 CTRL、127 PD/GBA、165 CTRL/GBA）。进行了差异表达分析、途径富集分析和离群值检测。还通过电子显微镜对四组分离的 CD14+单核细胞进行了超微结构特征描述。
我们观察到，在比较有症状和无症状 GBA 突变携带者时，有数百个差异表达基因和失调途径。具体而言，与特发性 PD 相比，PD/GBA 显示与α-突触核蛋白降解、衰老和淀粉样蛋白处理相关的基因失调。基于基因的离群值分析证实了溶酶体、膜转运和线粒体处理在表现型与非表现型 GBA 携带者中的参与，在超微结构水平也观察到了这一点。全血样本的独立队列中的转录组结果仅部分复制，表明存在细胞类型特异性变化。
总的来说，我们对原代单核细胞的转录组分析确定了基因靶标和生物学过程，这有助于理解与 PD 中 GBA 突变相关的致病机制。
