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bioRxiv · 10.1101/2025.06.23.661105

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

Chakraborty, R.·Maya, S.·Testa, V.·Montero-Munoz, J.·Nonaka, T.·Hasegawa, M.·Consiglio, A.·Zurzolo, C.
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Abstract

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.

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Chakraborty, R., Maya, S., Testa, V., Montero-Munoz, J., Nonaka, T., Hasegawa, M., Consiglio, A., Zurzolo, C.. 2025-06-24. α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication. https://doi.org/10.1101/2025.06.23.661105

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