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

帕金森氏病(PD)的定义是其显著的运动症状，包括震颤，僵硬， 运动迟缓和姿势不稳是由黑质多巴胺能(DA)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性震颤或 不是在疾病发作时。起病时有静止性震颤的帕金森病患者一般进展较慢，病情较好 帕金森病患者起病时无静息震颤的预后优于无静息震颤的患者。我们的初步研究表明， 控制多巴胺合成、隔离和降解的基因在 正常人与特发性帕金森病患者诱导多能干细胞来源的中脑DA神经元 病人。其中一些基因在特发性帕金森病患者中的表达也有显著差异 发作时有或没有静止性震颤。我们已经开发了一系列新技术，包括 IPSCs向A9 DA神经元分化及人皮肤成纤维细胞和尿路的直接转化 细胞(UTCs)至中脑DA神经元。利用这些创新技术，该提案旨在确定 分子标记可以区分PD患者和正常受试者，并区分患有或 起病时无静息震颤。干细胞技术的融合发展使这个项目能够 确定特发性帕金森病的分子特征，这将显著促进帕金森病的诊断， 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.