Astrocytic Ceruloplasmin Deficiency Triggers Iron Toxicity and Neurodegeneration in a LRRK2 Parkinson's Tri-Culture Model
Testa, V.; Montero-Munoz, J.; Baruffi, V.; Alzeer, M.; Mularoni, L.; Fernandez-Carasa, I.; Simmini, G.; Comellas-Comaposada, N.; Ake, F. A.; Richaud, Y.; Weissleder, C.; Amengual, J.; Fabregat, I.; Deleidi, M.; Plass, M.; Pluchino, S.; Raya, A.; Consiglio, A.
Show abstract
Astrocytes and microglia carrying the LRRK2-G2019S mutation contribute to non-cell- autonomous dopaminergic neuron (DAn) degeneration in Parkinsons 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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