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ePoster
LRRK2 INHIBITION INCREASES UPTAKE OF ALPHA-SYNUCLEIN FIBRILS IN HUMAN IPSC-DERIVED MICROGLIA
Josefine Fussing Tengbergand 5 co-authors
H. Lundbeck A/S
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS03-08AM-066
Presentation
Date TBA
Board: PS03-08AM-066
Event Information
Poster Board
PS03-08AM-066
Poster
View posterAbstract
Alpha-synuclein (αSyn) aggregates and inclusions in neurons are hallmarks of Parkinson’s disease (PD). Microglia may contribute to αSyn aggregate brain homeostasis by phagocytosing extracellular αSyn. This αSyn clearance may be influenced by neuroinflammation and genetic risk factors for PD, including Leucine-Rich Repeat Kinase 2 (LRRK2). To investigate how inflammatory stimuli and LRRK2 kinase inhibition affect the uptake of αSyn preformed fibrils (PFFs) in microglia, we utilised human induced pluripotent stem cell (iPSC)-derived microglia from both a healthy donor and a PD patient donor carrying the LRRK2 G2019S mutation. Cellular responses were assessed using RNA sequencing and immunoblotting, while αSyn PFF uptake was quantified using confocal and live-cell imaging. The pro-inflammatory cytokine interferon-gamma (IFNγ) markedly increased LRRK2 expression and kinase activity while significantly reducing αSyn PFF uptake in iPSC-derived microglia. Importantly, treatment with the selective LRRK2 kinase inhibitor MLi-2 partially reversed the IFNγ-induced suppression of αSyn PFF uptake in microglia from both donor types. In conclusion, our findings demonstrate that LRRK2 inhibition modulates αSyn PFF uptake under IFNγ-driven inflammatory conditions and highlight the interplay between neuroinflammation, LRRK2 activity, and pathological αSyn in PD.
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