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Abstract：
The diagnosis of Parkinson\'s disease (PD) is initiated after the occurrence of motor symptoms, such as resting tremors, rigidity, and bradykinesia. According to previous reports, non-motor symptoms, notably gastrointestinal dysfunction, could potentially be early biomarkers in PD patients as such symptoms occur earlier than motor symptoms. However, connecting PD to the intestine is methodologically challenging. Thus, we generated in vitro human intestinal organoids from PD patients and ex vivo mouse small intestinal organoids from aged transgenic mice. Both intestinal organoids (IOs) contained the human LRRK2 G2019S mutation, which is the most frequent genetic cause of familial and sporadic PD. By conducting comprehensive genomic comparisons with these two types of IOs, we determined that a particular gene, namely, Iroquois homeobox protein 2 (IRX2), showed PD-related expression patterns not only in human pluripotent stem cell (PSC)-derived neuroectodermal spheres but also in human PSC-derived neuronal cells containing dopaminergic neurons. We expected that our approach of using various cell types presented a novel technical method for studying the effects of multi-organs in PD pathophysiology as well as for the development of diagnostic markers for PD.
摘要：
帕金森病（PD）的诊断是在运动症状发生后开始的，比如静止的震颤，刚性,和运动迟缓.根据以前的报道，非运动症状,尤其是胃肠功能紊乱,可能是PD患者的早期生物标志物，因为这些症状比运动症状更早出现。然而,将PD连接到肠道在方法上具有挑战性。因此，我们从PD患者体内体外产生人肠器官，并从老年转基因小鼠体内产生小鼠小肠器官。两种肠道类器官（IOs）都含有人类LRRK2G2019S突变，这是家族性和散发性PD最常见的遗传原因。通过对这两种类型的IO进行全面的基因组比较，我们确定了一个特定的基因，即,易洛魁同源异型盒蛋白2（IRX2），不仅在人多能干细胞（PSC）衍生的神经外胚层球中，而且在含有多巴胺能神经元的人PSC衍生的神经元细胞中显示了PD相关的表达模式。我们期望我们使用各种细胞类型的方法为研究多器官在PD病理生理学中的作用以及开发PD诊断标志物提供了一种新颖的技术方法。
