Molecular Segregation of Parkinson’s Disease by Patient-derived Neurons

帕金森氏病（PD）由其标志性运动症状定义，包括震颤、僵硬， 运动迟缓和姿势不稳定，这是由黑质多巴胺能（DA）的进行性丧失引起的 神经元帕金森病的一个公认的分类是基于是否存在静息震颤或 而不是在发病时。发作时有静止性震颤的PD患者通常进展较慢， PD患者发病时无静息震颤。我们的初步研究表明， 控制多巴胺合成、螯合和降解的基因在 源自正常受试者与特发性PD的诱导多能干细胞（iPSC）的中脑DA神经元 患者其中一些基因的表达在特发性PD患者之间也有显著差异 发作时伴有或不伴有静止性震颤。我们开发了一系列新技术，包括 iPSC向A9 DA神经元的分化以及人皮肤成纤维细胞和尿道的直接转化 细胞（UTCs）到中脑DA神经元。利用这些创新技术，该提案旨在确定 可以分离PD患者和正常受试者的分子特征，并区分PD患者或 发作时无静息震颤。干细胞技术的融合发展使该项目能够 识别特发性帕金森病的分子特征，这将显著推进PD诊断， 研究和治疗开发。

Parkinson’s disease (PD) is defined by its hallmark locomotor symptoms including tremor, rigidity, bradykinesia and postural instability, which are caused by a progressive loss of nigral dopaminergic (DA) neurons. A well-recognized categorization of Parkinson’s disease is based on whether rest tremor is present or not at disease onset. PD patients who have rest tremor at onset generally have slower progression and better prognosis than PD patients without rest tremor at onset. Our preliminary study showed that the expression of genes controlling dopamine synthesis, sequestration and degradation was significantly different between midbrain DA neurons derived from induced pluripotent stem cells (iPSC) of normal subjects vs. idiopathic PD patients. Expression of some of these genes was also significantly different between idiopathic PD patients with or without rest tremor at onset. We have developed a series of new technologies including the differentiation of iPSCs to A9 DA neurons and the direct conversion of human skin fibroblasts and urinary track cells (UTCs) to midbrain DA neurons. Using these innovative technologies, the proposal aims to identify molecular signatures that can segregate PD patients and normal subjects, and distinguish PD patients with or without rest tremor at onset. The converging development of stem cell technologies enables this project to identify molecular signatures of idiopathic Parkinson’s disease, which will significantly advance PD diagnosis, research and therapeutic development.