Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patient. Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patient

Several mutations that cause Parkinson’s disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology. RNA sequencing Overall design: Shani Stern

过去十年间，研究人员已鉴定出多种可引发帕金森病（Parkinson’s Disease, PD）的基因突变。此类突变相关病例占帕金森病总病例的15%~25%，剩余病例则被归类为散发性帕金森病。当前学界普遍认为，帕金森病并非单一的同质疾病，而是一组具有部分共同表型的疾病群。尽管部分致病突变已成功构建啮齿类动物模型，但由于缺乏合适的细胞模型，针对散发性帕金森病的研究进展相对滞后。在本研究中，我们从携带多种帕金森病致病突变的患者以及散发性帕金森病患者的诱导多能干细胞（induced pluripotent stem cells, iPSCs）中分化得到了多巴胺能（dopaminergic, DA）神经元。令人瞩目的是，我们观察到了共通的神经生理学表型：与健康对照组来源的神经元相比，帕金森病患者来源的神经元其突触电流速率出现了显著降低。此前已有研究探讨了SNCA、LRRK2等基因的突变与突触传递功能降低之间的关联，但本研究证实，神经元突触的病理改变是帕金森病的一类普遍性表型。对RNA测序结果的分析显示，多种突触相关机制以及细胞外基质相关通路等其他受影响通路的基因表达均发生了改变。其中部分失调通路在所有帕金森病患者（包括单基因突变型与特发性患者）中均存在。因此，本研究的数据表明，这些改变是帕金森病的核心且汇聚性的病理特征，并提示四联体突触（tetra-partite synapse）在帕金森病病理生理过程中发挥着关键作用。RNA测序 整体实验设计：沙尼·斯特恩