Uptake of alpha-synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia

Abstract Microglia are brain resident immune cells that maintain proteostasis and cellular homeostasis. Recent findings suggest that microglia dysfunction could contribute to the pathogenesis of Parkinson’s disease. One of the hallmarks of Parkinson’s disease is the aggregation and accumulation of alpha-synuclein into Lewy bodies inside nerve cells. Microglia may worsen the neuronal microenvironment by persistent inflammation, resulting in deficient clearing of aggregated alpha-synuclein. To model microglial behavior in Parkinson’s disease, we utilized human induced pluripotent stem cells to generate functionally active microglia. We studied the microglial uptake of alpha-synuclein preformed fibrils (PFFs) and the effect of pro-inflammatory stimulation by interferon gamma. We demonstrate that combined exposure disrupts the phagosome maturation pathway while inflammatory stimuli suppress chaperone mediated autophagy and mitochondrial function. Furthermore, inflammatory stimulation impairs PFF uptake in microglia and increases cytokine production. Moreover, excessive PFF uptake by microglia results in induction of iNOS. Taken together, we demonstrate that this model is valuable for investigating the behavior of microglia in Parkinson’s disease and provide new insights on how human microglia process aggregated alpha-synuclein.