在 3D 中脑类器官中建立 G2019S-LRRK2 散发性帕金森病模型。
Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids.
机构信息
Laboratory of Stem Cells & Cell Reprogramming, Department of Biomedical Engineering (BK21Plus Team), Center for Regenerative Medicine, BK21Plus Team for Regenerative Medicine, Dongguk University, Pildong-ro 1-gil 30, Jung-gu, Seoul 04620, Republic of Korea.
Database Laboratory, Department of Computer Science and Engineering, Dongguk University, Pildong-ro 1-gil 30, Jung-gu, Seoul 04620, Republic of Korea.
出版信息
Stem Cell Reports. 2019 Mar 5;12(3):518-531. doi: 10.1016/j.stemcr.2019.01.020. Epub 2019 Feb 21.
Recent advances in generating three-dimensional (3D) organoid systems from stem cells offer new possibilities for disease modeling and drug screening because organoids can recapitulate aspects of in vivo architecture and physiology. In this study, we generate isogenic 3D midbrain organoids with or without a Parkinson's disease-associated LRRK2 G2019S mutation to study the pathogenic mechanisms associated with LRRK2 mutation. We demonstrate that these organoids can recapitulate the 3D pathological hallmarks observed in patients with LRRK2-associated sporadic Parkinson's disease. Importantly, analysis of the protein-protein interaction network in mutant organoids revealed that TXNIP, a thiol-oxidoreductase, is functionally important in the development of LRRK2-associated Parkinson's disease in a 3D environment. These results provide proof of principle for the utility of 3D organoid-based modeling of sporadic Parkinson's disease in advancing therapeutic discovery.
近年来，从干细胞中生成三维（3D）类器官系统为疾病建模和药物筛选提供了新的可能性，因为类器官可以重现体内结构和生理的某些方面。在这项研究中，我们生成了具有或不具有帕金森病相关 LRRK2 G2019S 突变的同基因 3D 中脑类器官，以研究与 LRRK2 突变相关的发病机制。我们证明这些类器官可以重现患者中观察到的 LRRK2 相关散发性帕金森病的 3D 病理特征。重要的是，突变体类器官中蛋白-蛋白相互作用网络的分析表明，TXNIP，一种硫醇氧化还原酶，在 3D 环境中 LRRK2 相关帕金森病的发展中具有重要的功能。这些结果为使用基于 3D 类器官的散发性帕金森病模型进行治疗发现提供了原理证明。
Zotero 插件