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

总结 痴呆是帕金森病（PD）的一种年龄依赖性共病， 80%的PD患者。对PD痴呆（PDD）的机制了解很少， 其与路易体痴呆（DLB）一起构成路易体痴呆（LBD）。 缺乏合适的模型系统严重阻碍了对这种复杂疾病的研究， 它与阿尔茨海默病（AD）有许多共同特征。在初步研究中，我们 开发了一种将诱导多能干细胞（iPSC）分化为皮质神经元的方法。 比较正常人和散发性阿尔茨海默病的皮质神经元 我们发现，TAU磷酸化显著增加， 突触基因的表达。在我们的父母R 01补助金中，我们开发了一种方法， 使iPSC分化为A9多巴胺能（DA）神经元。在中脑DA神经元中，来自 正常受试者和特发性PD患者，我们已经发现显着差异， 处理多巴胺的基因的表达。基于这些发现，我们假设， 来自LBD患者的iPSC衍生的皮质神经元和A9多巴胺能神经元可能表现出 分子和细胞特征与正常受试者显著不同。 三个具体的目标将被解决，以测试的假设，它扩展了父母R 01 在此行政补充申请中授予痴呆症。我们将生成大脑皮层 来自LBD患者和正常受试者的iPSC的A9 DA神经元（Aim 1）和A9 DA神经元（Aim 2）， 检查TAU和β-突触核蛋白的磷酸化和聚集状态，并比较 全球基因表达谱。我们将在尸检组织中确认关键发现， 目的3：观察LBD患者和正常人颞叶皮质和黑质的变化。信息 在这项集中的研究中产生的将为使用LBD生物标志物的发现奠定基础 患者源性神经元。研究中确定的关键靶点可以在药物发现中得到验证 使用患者源性皮质激素治疗LBD的认知、记忆和运动症状的努力 神经元或A9 DA神经元。行政补充申请将移动字段 通过识别区分LBD与正常受试者的分子和细胞特征， 在病人源性神经元和死后组织中。

Summary Dementia is an age-dependent co-morbidity of Parkinson’s disease (PD) that affects up to 80% of PD patients. There is very little mechanistic understanding of PD Dementia (PDD), which together with Dementia with Lewy Body (DLB), constitute Lewy Body Dementia (LBD). The lack of a suitable model system significantly hampers the study of this complex disorder, which shares many features with Alzheimer’s disease (AD). In our preliminary study, we developed a method to differentiate induced pluripotent stem cells (iPSCs) to cortical neurons. Comparing cortical neurons derived from normal subjects and sporadic Alzheimer’s disease patients, we found significant increases in TAU phosphorylation and significant decreases in the expression of synaptic genes. In our parental R01 grant, we have developed a method to differentiate iPSCs to A9 dopaminergic (DA) neurons. In midbrain DA neurons derived from normal subjects and idiopathic PD patients, we have found significant differences in the expression of genes handling dopamine. Premised on these findings, we hypothesize that iPSC-derived cortical neurons and A9 dopaminergic neurons from LBD patients may exhibit molecular and cellular features that are significantly different from those of normal subjects. Three specific aims will be addressed to test the hypothesis, which extends the parental R01 grant to dementia in this administrative supplement application. We will generate cortical neurons (Aim 1) and A9 DA neurons (Aim 2) from iPSCs of LBD patients and normal subjects to examine the phosphorylation and aggregation states of TAU and -synuclein, and compare the global gene expression profile. We will confirm key findings in postmortem tissues from middle temporal cortex and substantia nigra of LBD patients and normal subjects (Aim 3). Information generated in this focused study will lay the foundation for discovery of LBD biomarkers using patient-derived neurons. Key targets identified in the study can be validated in drug discovery efforts to address cognitive, memory and motor symptoms of LBD using patient-derived cortical neurons or A9 DA neurons. The administrative supplement application will move the field forward by identifying molecular and cellular features that distinguish LBD from normal subjects in patient-derived neurons and postmortem tissues.