Human microglia clear intraneuronal α-synuclein aggregates by GPNMB-mediated trogocytosis

Microglia are the primary immune cells of the brain, but their role in Parkinson's disease is not fully understood. Chronic microglial activation is toxic to neurons, but in the early stages of pathology, microglia also exert beneficial functions. We used induced pluripotent stem cell (iPSC)-derived coculture models to investigate how human microglia respond to α-synuclein aggregates that form de novo inside human dopaminergic neurons with α-synuclein gene triplication or are triggered by fibrils. We found that microglia cleared Ser¹²⁹-phosphorylated α-synuclein aggregates through a contact-dependent mechanism. This process was fine-tuned by sensing (P2RY12) and inhibitory (CD22) signals and involved selective phagocytosis of neuronal subcompartments (trogocytosis), independently of TREM2 or phosphatidylserine. In the presence of intraneuronal α-synuclein aggregates, microglia exhibited morphological and transcriptional changes indicative of activation. Using single-cell sequencing, we identified a cluster of disease-associated microglia (DAM) responsible for this beneficial phenotype and the Parkinson's disease GWAS candidate glycoprotein nonmetastatic melanoma protein B (GPNMB) as a key effector of aggregate clearance by microglial lysosomes. GPNMB interacted with Ser¹²⁹-phosphorylated α-synuclein in iPSC-derived microglia exposed to aggregate-laden dopaminergic neurons and was up-regulated in substantia nigra microglia of individuals with incidental Lewy bodies or Parkinson's disease. Microglia-specific GPNMB knockdown using CRISPRi reduced intraneuronal aggregate clearance. GPNMB-mediated trogocytosis was negatively regulated by an autocrine IL-10 signaling loop, whereas IL-10 receptor blockade enhanced the phagocytic response. Together, our study identifies a subtype of human microglia capable of removing intraneuronal aggregates and potential therapeutic targets.