α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication

Tunneling nanotubes (TNTs) enable direct intercellular transfer of macromolecules, organelles, and pathogenic protein aggregates. While -synuclein (-Syn) aggregates are known to promote TNT formation, the underlying mechanisms remain poorly defined. Here, using human neuronal and microglial cell lines, as well as iPSC-derived dopaminergic neurons and microglia, we show that -Syn aggregates induce severe mitochondrial damage, leading to cytosolic release of mitochondrial DNA (mtDNA) and activation of the cGAS-STING-NF- {kappa}B-IRF3 pathway. This innate immune response drives actin cytoskeleton remodeling and the formation of TNT-like structures, promoting intercellular transfer of -Syn from neurons to microglia. Additionally, neuronal cells transfer damaged mitochondria to microglia, where they undergo lysosome-mediated degradation. Neuron-to-microglia communication under -Syn- induced stress also triggers a bystander inflammatory response in microglia, suggesting a neuroimmune activation. Our findings identify mitochondrial damage and STING-mediated inflammation as key drivers of TNT formation and -Syn propagation, highlighting new potential targets to modulate disease progression in Synucleinopathies.