Human microglia remove intraneuronal a-synuclein aggregates in a stem cell model of Parkinson’s disease

Microglia are the primary immune cells of the brain but their role in Parkinson’s disease is not fully understood. Although most studies suggest that chronic microglial activation is toxic to neurons, they also exert beneficial functions in the early stages of neuronal pathology that are not yet well defined. We used iPSC modelling to investigate how human microglia respond to α-synuclein aggregation that forms de novo in human dopaminergic neurons with α-synuclein gene triplication or is triggered by fibrils. We found that microglia cleared Ser129 phosphorylated α-synuclein aggregates without exacerbating neurotoxicity, using a contact-dependent mechanism involving selective phagocytosis (i.e. trogocytosis) of neuronal sub-compartments that is independent of TREM2 or phosphotidylserine. In the presence of intraneuronal α-synuclein aggregates, microglia exhibited morphological changes and transcriptomic profiles indicative of activation. Using single cell sequencing, we identified a sub-cluster of disease-associated microglia (DAM) in association with this phenotype, and GPNMB as a key effector of a-synuclein aggregate clearance by microglial lysosomes. Importantly, our secretome analysis suggests that the identified DAM sub-cluster is negatively regulated by an autocrine loop mechanism involving IL-10 and blocking this pathway using antibodies promotes the phagocytic response. Taken together, our study identifies a specific microglial subtype that exerts beneficial trogocytic effects on human dopaminergic neurons containing α-synuclein aggregates and suggests that stabilisation of such subpopulations during the neurodegenerative process could be a useful therapeutic strategy.