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

Hongwon Kim; Hyeok Ju Park; Hwan Choi; Yujung Chang; Hanseul Park; Jaein Shin; Junyeop Kim; Christopher J Lengner; Yong Kyu Lee; Jongpil Kim

doi:10.1016/j.stemcr.2019.01.020

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

Stem Cell Reports. 2019 Mar 5;12(3):518-531. doi: 10.1016/j.stemcr.2019.01.020. Epub 2019 Feb 21.

Authors

Affiliations

¹ 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.
² Database Laboratory, Department of Computer Science and Engineering, Dongguk University, Pildong-ro 1-gil 30, Jung-gu, Seoul 04620, Republic of Korea.
³ Department of Biomedical Sciences, School of Veterinary Medicine and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ 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; Department of Chemistry, Dongguk University, Pildong-ro 1-gil 30, Jung-gu, Seoul 04620, Republic of Korea. Electronic address: jpkim153@dongguk.edu.

Abstract

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.

Keywords: Parkinson's disease; disease modeling; iPSC; midbrain; organoids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cells, Cultured
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
Male
Middle Aged
Mutation / genetics
Organoids / cytology*
Parkinson Disease / genetics*
Parkinson Disease / therapy*

Substances

LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2