MLi-2 Dose-Response Curve in LRRK2 G2019S mutated iPSC-derived microglia

Document Type

Article

Publication Date

2026

JAX Location

NYSCF

Abstract

Parkinson’s disease involves neuroinflammation and alpha-synuclein accumulation, often cleared by healthy microglia. The LRRK2 G2019S mutation causes genetic kinase hyperactivation, disrupting endolysosomal clearance and cellular trafficking. This research investigates the effects of the selective small-molecule kinase inhibitor MLi-2 on G2019S mutant microglia challenged with alpha-synuclein pre-formed fibrils. Adherent cultures were pre-treated with MLi-2 (12.5 nM to 100 nM) for 2 hours before receiving a 5 µg/mL fluorescent fibril challenge. High-resolution multi-channel z-stack tracking was conducted using the Opera Phenix system, paired with automated 3D surface masking to map spatial proximity profiles across nuclear, cytoplasmic, and fibril channels. Imaging revealed a trend-level stabilization of mutant cell layers within the 50 nM to 100 nM treatment range. While selective kinase inhibition influenced mutant cellular trafficking profiles, current data do not establish functional rescue or definitive kinase saturation. Interpretation of these baseline findings remains cautious due to technical limitations imposed by threshold masking on the tracking software and cell density variations across duplicate replicate wells.

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