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.

在过去的十年里，已经发现了几种导致帕金森病 (PD) 的突变。这些占 PD 病例的 15-25%；其余病例被视为散发病例。目前，人们普遍认为帕金森病不是一种单一的整体疾病，而是具有一些常见表型的疾病群。虽然存在一些导致帕金森病的突变的啮齿动物模型，但由于缺乏细胞模型，对散发性帕金森病的研究却滞后。在我们的研究中，我们将帕金森病患者来源的多巴胺能 (DA) 神经元与几种帕金森病引起突变的诱导多能干细胞 (iPSC) 以及散发性帕金森病患者区分开来。引人注目的是，我们观察到了一个常见的神经生理学表型：与来自健康对照的神经元相比，来自帕金森病患者的神经元的突触电流速率严重降低。虽然之前已经研究过SNCA和LRRK2等基因突变与突触传递减少之间的关系，但在这里我们证明神经元突触的发病机制是 PD 的普遍表型。 RNA测序结果分析显示不同突触机制以及其他受影响途径（例如细胞外基质相关途径）中基因表达的变化。其中一些失调途径对于所有 PD 患者（单基因或特发性）都是常见的。因此，我们的数据显示了 PD 的核心和汇聚变化，并表明四部分突触在 PD 病理生理学中发挥着重要作用。