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ASTROCYTIC CERULOPLASMIN DEFICIENCY TRIGGERS IRON TOXICITY AND NEURODEGENERATION IN A LRRK2 PARKINSON’S TRI-CULTURE MODEL
Veronica Testaand 17 co-authors
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS03-08AM-063
Presentation
Date TBA
Board: PS03-08AM-063
Event Information
Poster Board
PS03-08AM-063
Poster
View posterAbstract
Astrocytes and microglia carrying the LRRK2-G2019S mutation contribute to non-cell-autonomous dopaminergic neuron (DAn) degeneration in Parkinson’s disease (PD), but the mechanisms underlying their interplay remain unclear. Here, we developed a novel induced pluripotent stem cell (iPSC)-derived tri-culture system comprising healthy DAn and either LRRK2-mutant or isogenic control iPSC-derived astrocytes and microglia. Using integrated functional assays and transcriptomic profiling, we found that mutant astrocytes adopt a hyperreactive state, driving microglial activation and subsequent DAn degeneration. Mechanistically, we identified a selective downregulation of ceruloplasmin (CP), a copper-dependent ferroxidase, in mutant astrocytes, leading to disrupted iron homeostasis with accumulation of Fe2+ and ROS. This iron dysregulation mediated both microglial reactivity and neurodegeneration. Notably, pharmacological restoration of CP re-established iron homeostasis, reduced microglial activation, and protected DAn from degeneration. Our findings uncover a novel astrocyte-microglia-neuron axis driving PD pathogenesis and showcase the power of our unique stem cell tri-culture platform for dissecting disease mechanisms and discovering therapeutic targets.
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