Parkinson’s disease microglia induce endogenous α-synuclein pathology in patient specific midbrain organoids.

Although considerable progress has been made in understanding α-synuclein's role in PD pathology, the precise mechanisms involved remain unclear. Human midbrain organoids (hMOs) have emerged as valuable models for studying PD, yet the lack of microglia limits the ability to investigate neuroimmune interactions.

Recent studies show that integrating microglia into hMOs enhances neuronal maturation and functionality. Here, we generated a human midbrain assembloid model by incorporating iPSC-derived microglia into midbrain organoids from healthy control individuals and a PD patient carrying the SNCA triplication (3xSNCA) mutation. Our results show that 3xSNCA microglia alone are sufficient to induce early, endogenous formation of phosphorylated α-synuclein (pS129) pathology in the absence of exogenous fibril seeding.