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

Authors#

Henry Kurniawan, Sarah L. Nickels, Alise Zagare, Elisa Zuccoli, Isabel Rosety, Gemma Gomez-Giro, Enrico Glaab, Jens C. Schwamborn

Abstract#

A growing body of evidence implicates inflammation as a key hallmark in the pathophysiology of Parkinson’s disease (PD), with microglia playing a central role in mediating neuroinflammatory signaling in the brain. However, the molecular mechanisms linking microglial activation to dopaminergic neuron degeneration remain poorly understood. In this study, we investigated the contribution of the PD-associated LRRK2-G2019S mutation to microglial neurotoxicity using patient-derived induced pluripotent stem cell (iPSC) models. We found that LRRK2-G2019S mutant microglia exhibited elevated activation markers, enhanced phagocytic capacity, and increased secretion of pro-inflammatory cytokines such as TNF-α. These changes were associated with metabolic dysregulation, including upregulated glycolysis and impaired serine biosynthesis. In 3D midbrain organoids, these overactivated microglia drove dopaminergic neuron degeneration. Notably, correcting the metabolic imbalance attenuated microglial inflammation and reversed neuronal loss. Our findings underscore the role of metabolic reprogramming in microglia as a driver of neurodegeneration and highlight a potential therapeutic avenue for PD.