Krauskopf Julian, Eggermont Kristel, Madeiro Da Costa Rodrigo Furtado, Bohler Sacha, Hauser Duncan, Caiment Florian, de Kok Theo M, Verfaillie Catherine, Kleinjans Jos C
Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands.
Stem Cell Institute, Department of Development and Regeneration, Katholieke Universiteit Leuven, Leuven, Belgium.
Mol Psychiatry. 2022 Oct;27(10):4355-4367. doi: 10.1038/s41380-022-01663-y. Epub 2022 Jun 20.
Parkinson's disease (PD) is a progressive, neurodegenerative disease affecting over 1% of the population beyond 65 years of age. Although some PD cases are inheritable, the majority of PD cases occur in a sporadic manner. Risk factors comprise next to heredity, age, and gender also exposure to neurotoxins from for instance pesticides and herbicides. As PD is characterized by a loss of dopaminergic neurons in the substantia nigra, it is nearly impossible to access and extract these cells from patients for investigating disease mechanisms. The emergence of induced pluripotent stem (iPSC) technology allows differentiating and growing human dopaminergic neurons, which can be used for in vitro disease modeling. Here, we differentiated human iPSCs into dopaminergic neurons, and subsequently exposed the cells to increasing concentrations of the neurotoxin MPP. Temporal transcriptomics analysis revealed a strong time- and dose-dependent response with genes over-represented across pathways involved in PD etiology such as "Parkinson's Disease", "Dopaminergic signaling" and "calcium signaling". Moreover, we validated this disease model by showing robust overlap with a meta-analysis of transcriptomics data from substantia nigra from post-mortem PD patients. The overlap included genes linked to e.g. mitochondrial dysfunction, neuron differentiation, apoptosis and inflammation. Our data shows, that MPP-induced, human iPSC-derived dopaminergic neurons present molecular perturbations as observed in the etiology of PD. Therefore we propose iPSC-derived dopaminergic neurons as a foundation for a novel sporadic PD model to study the pathomolecular mechanisms of PD, but also to screen for novel anti-PD drugs and to develop and test new treatment strategies.
帕金森病（PD）是一种进行性神经退行性疾病，影响着超过1%的65岁以上人群。虽然一些帕金森病病例是可遗传的，但大多数病例以散发性方式出现。风险因素除了遗传、年龄和性别外，还包括接触来自农药和除草剂等的神经毒素。由于帕金森病的特征是黑质中多巴胺能神经元的丧失，几乎不可能从患者体内获取和提取这些细胞来研究疾病机制。诱导多能干细胞（iPSC）技术的出现使得人类多巴胺能神经元得以分化和生长，可用于体外疾病建模。在此，我们将人类iPSC分化为多巴胺能神经元，随后将细胞暴露于浓度不断增加的神经毒素MPP中。时间转录组学分析揭示了一种强烈的时间和剂量依赖性反应，涉及帕金森病病因的通路中基因过度表达，如“帕金森病”、“多巴胺能信号传导”和“钙信号传导”。此外，我们通过与死后帕金森病患者黑质转录组学数据的荟萃分析显示出强烈重叠来验证了这个疾病模型。重叠的基因包括与线粒体功能障碍、神经元分化、细胞凋亡和炎症等相关的基因。我们的数据表明，MPP诱导的、源自人类iPSC的多巴胺能神经元呈现出帕金森病病因中观察到的分子扰动。因此，我们提出源自iPSC的多巴胺能神经元作为一种新型散发性帕金森病模型的基础，用于研究帕金森病的病理分子机制，还可用于筛选新型抗帕金森病药物以及开发和测试新的治疗策略。
