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

Human microglia clear intraneuronal α-synuclein aggregates via GPNMB-mediated trogocytosis, with GPNMB up-regulation linked to disease-associated microglia in Parkinson's disease.

• Why it matters: Understanding microglial roles in Parkinson's disease is crucial because their activation can be both toxic and beneficial, but the mechanisms of aggregate clearance remain unclear. Clarifying these processes could inform therapeutic strategies to modulate microglial responses.
• What they did: Using iPSC-derived coculture models, the study investigated microglial responses to α-synuclein aggregates, identifying GPNMB as a key effector in lysosomal clearance and characterizing microglial activation and phenotypes through single-cell sequencing and CRISPRi knockdown.
• The result: GPNMB interacts with phosphorylated α-synuclein and is up-regulated in Parkinson's disease microglia; GPNMB knockdown reduces aggregate clearance, suggesting it as a potential therapeutic target for enhancing microglial removal of neuronal aggregates.