Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Cells. 2023 Feb 15;12(4):625. doi: 10.3390/cells12040625.
Progressive accumulation of α-Synuclein (αSyn) in Lewy bodies (LBs) and loss of dopaminergic (DA) neurons are the hallmark pathological features of Parkinson's disease (PD). Although currently available in vitro and in vivo models have provided crucial information about PD pathogenesis, the mechanistic link between the progressive accumulation of αSyn into LBs and the loss of DA neurons is still unclear. To address this, it is critical to model LB formation and DA neuron loss, the two key neuropathological aspects of PD, in a relevant in vitro system. In this study, we developed a human midbrain-like organoid (hMBO) model of PD. We demonstrated that hMBOs generated from induced pluripotent stem cells (hiPSCs), derived from a familial PD (fPD) patient carrying αSyn gene () triplication accumulate pathological αSyn over time. These cytoplasmic inclusions spatially and morphologically resembled diverse stages of LB formation and were composed of key markers of LBs. Importantly, the progressive accumulation of pathological αSyn was paralleled by the loss of DA neurons and elevated apoptosis. The model developed in this study will complement the existing in vitro models of PD and will provide a unique platform to study the spatiotemporal events governing LB formation and their relation with neurodegeneration. Furthermore, this model will also be beneficial for in vitro screening and the development of therapeutic compounds.
α-突触核蛋白（αSyn）在路易体（LB）中的逐渐积累和多巴胺能（DA）神经元的丧失是帕金森病（PD）的标志性病理特征。尽管目前可用的体外和体内模型提供了有关 PD 发病机制的重要信息，但 αSyn 逐渐积累到 LB 中和 DA 神经元丧失之间的机制联系仍不清楚。为了解决这个问题，在相关的体外系统中对 LB 形成和 DA 神经元丧失这两个 PD 的关键神经病理学方面进行建模至关重要。在这项研究中，我们开发了一种 PD 的人类中脑细胞类器官（hMBO）模型。我们证明了源自携带 αSyn 基因（）三重复制的家族性 PD（fPD）患者的诱导多能干细胞（hiPSC）生成的 hMBO 随着时间的推移会积累病理性 αSyn。这些细胞质内含物在空间和形态上类似于 LB 形成的不同阶段，并且由 LB 的关键标志物组成。重要的是，病理性 αSyn 的逐渐积累伴随着 DA 神经元的丧失和凋亡的增加。本研究中开发的模型将补充现有的 PD 体外模型，并为研究控制 LB 形成的时空事件及其与神经退行性变的关系提供独特的平台。此外，该模型也有利于体外筛选和治疗化合物的开发。
