Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States; Department of Cell Systems & Anatomy, TX, United States.
Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States; Department of Cell Systems & Anatomy, TX, United States; Department of Radiology, University of Texas Health Science Center at San Antonio, TX, United States.
Brain Res. 2019 Nov 1;1722:146342. doi: 10.1016/j.brainres.2019.146342. Epub 2019 Jul 19.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by the loss of the midbrain dopaminergic neurons, which leads to impaired motor and cognitive functions. PD is predominantly an idiopathic disease, however about 5% of cases are linked to hereditary mutations. The most common mutation in both familial and sporadic PD is the G2019S mutation of leucine-rich repeat kinase 2 (LRRK2) with high prevalence in Ashkenazi Jewish patients and in North African Berber and Arab patients. It is still not fully understood how this mutation leads to PD pathology. In this study, we derived induced pluripotent stem cells (iPSCs) from an Ashkenazi Jewish patient with G2019S LRRK2 mutation to isolate self-renewable multipotent neural stem cells (NSCs) and to model this form of PD in vitro. To investigate the cellular diversity and disease pathology in the NSCs, we used single cell RNA-seq transcriptomic profiling. The evidence suggests there are three subpopulations within the NSCs: a committed neuronal population, intermediate stage population and undifferentiated stage population. Unbiased single-cell transcriptomic analysis revealed differential expression and dysregulation of genes involved in PD pathology. The significantly affected genes were involved in mitochondrial function, DNA repair, protein degradation, oxidative stress, lysosome biogenesis, ubiquitination, endosome function, autophagy and mitochondrial quality control. The results suggest that G2019S LRRK2 mutation may affect multiple cell types in a non-cell autonomous mechanism of PD pathology and that unbiased single-cell transcriptomics holds promise for personalized medicine.
帕金森病（PD）是第二大常见的神经退行性疾病，其特征是中脑多巴胺能神经元丧失，导致运动和认知功能受损。PD 主要是一种特发性疾病，然而约 5%的病例与遗传性突变有关。在家族性和散发性 PD 中最常见的突变是富含亮氨酸重复激酶 2（LRRK2）的 G2019S 突变，在阿什肯纳兹犹太患者以及北非柏柏尔人和阿拉伯患者中发病率很高。目前尚不完全清楚这种突变如何导致 PD 病理学。在这项研究中，我们从一名患有 G2019S LRRK2 突变的阿什肯纳兹犹太 PD 患者中获得诱导多能干细胞（iPSC），以分离自我更新的多能神经干细胞（NSC），并在体外模拟这种形式的 PD。为了研究 NSCs 中的细胞多样性和疾病病理学，我们使用了单细胞 RNA-seq 转录组谱分析。证据表明 NSCs 中有三个亚群：一个定向神经元群体、中间阶段群体和未分化阶段群体。无偏单细胞转录组分析显示，涉及 PD 病理学的基因表达存在差异和失调。受显著影响的基因涉及线粒体功能、DNA 修复、蛋白质降解、氧化应激、溶酶体生物发生、泛素化、内体功能、自噬和线粒体质量控制。结果表明，G2019S LRRK2 突变可能以非细胞自主的 PD 病理学机制影响多种细胞类型，无偏单细胞转录组学为个性化医疗提供了希望。
