Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids

被引：239
作者：
Kim, Hongwon [1 ]
Park, Hyeok Ju [3 ]
Choi, Hwan [1 ]
Chang, Yujung [1 ]
Park, Hanseul [1 ]
Shin, Jaein [1 ]
Kim, Junyeop [1 ]
Lengner, Christopher J. [4 ,5 ]
Lee, Yong Kyu [3 ]
Kim, Jongpil [1 ,2 ]
机构：
[1] Dongguk Univ, BK21Plus Team Regenerat Med, Lab Stem Cells & Cell Reprogramming, Dept Biomed Engn,BK21Plus Team,Ctr Regenerat Med, Pildong Ro 1 Gil 30, Seoul 04620, South Korea
[2] Dongguk Univ, Dept Chem, Pildong Ro 1 Gil 30, Seoul 04620, South Korea
[3] Dongguk Univ, Dept Comp Sci & Engn, Database Lab, Pildong Ro 1 Gil 30, Seoul 04620, South Korea
[4] Univ Penn, Sch Vet Med, Dept Biomed Sci, Philadelphia, PA 19104 USA
[5] Univ Penn, Inst Regenerat Med, Philadelphia, PA 19104 USA
来源：
STEM CELL REPORTS | 2019年 / 12卷 / 03期
基金：
新加坡国家研究基金会;
关键词：
TRANSGENIC MOUSE MODEL; ALPHA-SYNUCLEIN; STEM-CELLS; SHARED FEATURE; LRRK2; GENE; ACCUMULATION; MUTATION; PATHWAY; BRAIN;
D O I：
10.1016/j.stemcr.2019.01.020
中图分类号：
Q813 [细胞工程];
学科分类号：
摘要：
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.
引用
收藏
页码：518 / 531
页数：14
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