The Parkinson's disease associated LRRK2-G2019S variant restricts serine metabolism leading to microglia inflammation and dopaminergic neuron degeneration

A mounting body of evidence reveals that inflammation is a major hallmark in the pathophysiology of Parkinson's disease (PD). Notably, microglia are key players in orchestrating neuroinflammatory signalling pathways in the brain. However, the molecular mechanisms underlying the microglial response in the dopaminergic neuron degeneration remain unclear. In this study, we investigated the role of the PD-associated LRRK2-G2019S variant in microglial neurotoxicity that potentially drives the loss of dopaminergic neurons. Using PD patient-specific induced pluripotent stem cell-based models, we showed that microglia harbouring the LRRK2-G2019S mutation exhibited increased activation markers, phagocytic capacity, and secretion of inflammatory cytokines such as TNF-a. This was linked to metabolic dysregulation, including higher levels of glycolysis and a reduction in serine biosynthesis. These overactivated microglia drove dopaminergic neuron degeneration in a 3D midbrain organoid model. Intriguingly, addressing the PD associated metabolic disturbances reduced the inflammatory state of the microglia and reversed neuronal loss. These findings reinforce the immunometabolic control of microglia to preserve dopaminergic neuron integrity and its pivotal role in PD pathogenesis. Overall design: Bulk RNAseq from iPSC-derived microglia of 4 Healthy and 4 PD patients carrying mutations in the LRRK2-G2019S gene