Advanced human iPSC-based preclinical model for Parkinson’s disease with optogenetic alpha-synuclein aggregation
- Authors
- Kim, Min Seong; Ra, Eun A.; Kweon, Sin Ho; Seo, Bo Am; Ko, Han Seok; Oh, Yohan; Lee, Gabsang
- Issue Date
- Jul-2023
- Publisher
- Cell Press
- Keywords
- Parkinson’s disease; alpha-synuclein; dopaminergic neurons; human pluripotent stem cell; opto-alpha-synuclein; optogenetics; organoid; protein aggregation; α-syn PFFs; α-synuclein preformed fibrils
- Citation
- Cell Stem Cell, v.30, no.7, pp.973 - 986
- Indexed
- SCIE
SCOPUS
- Journal Title
- Cell Stem Cell
- Volume
- 30
- Number
- 7
- Start Page
- 973
- End Page
- 986
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/187559
- DOI
- 10.1016/j.stem.2023.05.015
- ISSN
- 1934-5909
- 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.
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