Advanced human iPSC-based preclinical model for Parkinson's disease with optogenetic alpha-synuclein aggregation
Min Seong Kim1, Eun A Ra1, Sin Ho Kweon1
1Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
A novel optogenetics-assisted system (OASIS) rapidly induces Parkinson's disease pathology in stem cells. This system identified BAG956, a drug that reverses disease symptoms by clearing toxic protein aggregates.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Pharmacology
Background:
- Human induced pluripotent stem cells (hiPSCs) are valuable for disease modeling but struggle to replicate late-onset neurodegenerative diseases like Parkinson's disease (PD).
- Recreating cellular pathologies, especially accumulated protein aggregates like alpha-synuclein (α-syn), remains a significant challenge in PD modeling.
- Existing models often fail to capture the complexity of PD pathogenesis, hindering effective drug discovery.
Purpose of the Study:
- To develop a novel system for rapidly inducing alpha-synuclein (α-syn) aggregation and toxicity in Parkinson's disease (PD) models.
- To utilize this system for high-throughput screening of potential therapeutic compounds.
- To identify and validate a drug candidate that can reverse PD phenotypes by promoting the clearance of pathological α-syn.
Main Methods:
- Development of an optogenetics-assisted α-synuclein (α-syn) aggregation induction system (OASIS).
- Application of OASIS for primary compound screening using SH-SY5Y cells and subsequent validation in PD hiPSC-midbrain dopaminergic neurons and organoids.
- In vitro and in vivo testing of the selected compound (BAG956) in α-syn preformed fibril models.
Main Results:
- OASIS successfully and rapidly induced α-syn aggregates and toxicity in PD hiPSC-derived neurons and organoids.
- Primary screening identified 5 drug candidates, with BAG956 selected after secondary validation.
- BAG956 demonstrated significant reversal of PD phenotypes in vitro and in vivo by enhancing autophagic clearance of pathological α-syn.
Conclusions:
- The OASIS system provides a robust and rapid method for modeling PD and screening for therapeutics.
- BAG956 is a promising therapeutic candidate for Parkinson's disease, effectively clearing toxic α-syn aggregates.
- OASIS serves as an effective animal-free preclinical test model for synucleinopathy drug development, aligning with modern regulatory trends.
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