Blasco-Agell, L.; Espinal, M. P.; Testa, V.; Roch, G.; Montero-Mu, J.; Fern, I.; Baruffi, V.; Gonzalez-Sepulveda, M.; Richaud-Patin, Y.; Jim, S.; Cuadros, T.; Cladera-Sastre, J. M.; Compte, J.; Otero, M. J.; Tolosa, E.; Raya, A.; Vila, M.; Consiglio, A.

Parkinson's disease (PD) is a progressive and yet incurable neurodegenerative condition characterized by loss of neuromelanin-containing dopamine neurons in the substantia nigra of the midbrain. The contribution of non-neuronal cells to neuron degeneration in PD is receiving increasing attention. Here, we generated functional microglia-like cells from induced pluripotent stem cells (iPSC) from patients with PD associated to LRRK2 mutations, the most common cause of genetic PD, along with their gene-corrected isogenic controls and with iPSC from healthy donors. Microglia-like cells of either genotype did not induce neurodegeneration of healthy dopamine neurons in co-culture experiments. However, LRRK2-mutant microglia became hyperreactive upon LPS stimulation when compared with controls, as judged by cytokine expression profile, production of reactive oxygen species. We then tested a-synuclein and neuromelanin as potential endogenous stimuli for activating mutant microglia. Upon exposure to neuromelanin-containing particles, but not to preformed a-synuclein fibrils, LRRK2-mutant microglia induced the degeneration of healthy dopamine neurons, in a process that could be prevented by pre-treatment with the immunomodulatory drug ivermectin. Finally, the analysis of post-mortem midbrain tissue of LRRK2-PD patients found increased numbers of activated microglia cells in close contact with neuromelanin-containing neurons. Taken together, our findings uncover a potential critical role of neuromelanin-activated microglia in the context of PD progression, and provide an experimental model of PD to test new therapeutic targets.