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

摘要 痴呆症是一种与年龄相关的帕金森氏病(PD)的共同发病，影响UP 至80%的帕金森病患者。对帕金森氏病痴呆(PDD)的机制了解很少， 与路易体痴呆(DLB)共同构成路易体痴呆(LBD)。 缺乏合适的模型系统大大阻碍了对这种复杂疾病的研究， 这与阿尔茨海默病(AD)有许多相似之处。在我们的初步研究中，我们 开发了一种将诱导多能干细胞(IPSCs)分化为皮质神经元的方法。 正常人和散发性阿尔茨海默病患者皮质神经元的比较 患者中，我们发现TAU磷酸化显著增加，而 突触基因的表达。在我们的父母R01赠款中，我们开发了一种方法来 将IPSCs分化为A9多巴胺能神经元。在中脑，DA神经元起源于 我们发现正常人和特发性帕金森病患者之间存在显著差异。 处理多巴胺的基因的表达。基于这些发现，我们假设 LBD患者的IPSC来源的皮质神经元和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。 将解决三个具体目标来检验该假说，该假说扩展了亲本R01 在此行政补充申请中授予痴呆症患者。我们会产生大脑皮层 LBD患者和正常人IPSCs的神经元(Aim 1)和A9 DA神经元(Aim 2) 检测TAU和-突触核蛋白的磷酸化和聚集态，并比较 全球基因表达谱。我们将从中期确认身体组织中的关键发现 LBD患者和正常人的颞叶皮质和黑质(目标3)。信息 这项重点研究中产生的数据将为发现LBD生物标志物奠定基础 病人来源的神经元。研究中确定的关键靶点可以在药物发现中得到验证 使用患者来源的皮质来解决LBD的认知、记忆和运动症状的努力 神经元或A9 DA神经元。行政补充申请将改变这一领域 通过识别LBD与正常受试者的分子和细胞特征进行研究 在病人来源的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.