오요한 (Johns Hopkins University School of Medicine, 한양대학교)

한빛사논문

조회554

Johns Hopkins University School of Medicine, 한양대학교

CV File 151 kb

Cell Stem Cell, June 19, 2023 | https://doi.org/10.1016/j.stem.2023.05.015 Advanced human iPSC-based preclinical model for Parkinson’s disease with optogenetic alpha-synuclein aggregation

Min Seong Kim, ^1,2,10 Eun A. Ra, ^1,2,10 Sin Ho Kweon, ^1,2,10 Bo Am Seo, ^1,3,4,5 Han Seok Ko, ^1,2,* Yohan Oh, ^1,6,7,8,* and Gabsang Lee ^1,2,9,11,*

¹Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
²Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
³Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju-si, Gangwon-do, Korea
⁴Department of Convergence Medicine, Yonsei University Wonju College of Medicine, Wonju-si, Gangwon-do, Korea
⁵Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju-si, Gangwon-do, Korea
⁶Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
⁷Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea
⁸Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
⁹Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
¹⁰These authors contributed equally
¹¹Lead contact

*Corresponding author: correspondence to Han Seok Ko, Yohan Oh or Gabsang Lee

Abstract

Human induced pluripotent stem cells (hiPSCs) offer advantages for disease modeling and drug discovery. However, recreating innate cellular pathologies, particularly in late-onset neurodegenerative diseases with accumulated protein aggregates including Parkinson’s disease (PD), has been challenging. To overcome this barrier, we developed an optogenetics-assisted α-synuclein (α-syn) aggregation induction system (OASIS) that rapidly induces α-syn aggregates and toxicity in PD hiPSC-midbrain dopaminergic neurons and midbrain organoids. Our OASIS-based primary compound screening with SH-SY5Y cells identified 5 candidates that were secondarily validated with OASIS PD hiPSC-midbrain dopaminergic neurons and midbrain organoids, leading us to finally select BAG956. Furthermore, BAG956 significantly reverses characteristic PD phenotypes in α-syn preformed fibril models in vitro and in vivo by promoting autophagic clearance of pathological α-syn aggregates. Following the FDA Modernization Act 2.0’s emphasis on alternative non-animal testing methods, our OASIS can serve as an animal-free preclinical test model (newly termed “nonclinical test”) for the synucleinopathy drug development.

논문정보

형식Research article
게재일2023년 06월 (BRIC 등록일 2023-06-21)
연구진국내(교신)+국외 연구진
분야 의약학 > 재생의학

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