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<p>Tunneling nanotubes (TNTs) enable direct intercellular transfer of macromolecules, organelles, and pathogenic protein aggregates. While <i>α</i>-synuclein (<i>α</i>-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 <i>α</i>-Syn aggregates induce severe mitochondrial damage, leading to cytosolic release of mitochondrial DNA (mtDNA) and activation of the cGAS–STING–NF-κB–IRF3 pathway. This innate immune response drives actin cytoskeleton remodeling and the formation of TNT-like structures, promoting intercellular transfer of <i>α</i>-Syn from neurons to microglia. Additionally, neuronal cells transfer damaged mitochondria to microglia, where they undergo lysosome-mediated degradation. Neuron-to-microglia communication under <i>α</i>-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 <i>α</i>-Syn propagation, highlighting potential targets to modulate disease progression in Synucleinopathies.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月15日

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  • Ranabir Chakraborty,
  • Stephanie Maya,
  • Veronica Testa,
  • Jara Montero-Muñoz,
  • Takashi Nonaka,
  • Masato Hasegawa,
  • Antonella Consiglio,
  • Chiara Zurzolo

摘要

Tunneling nanotubes (TNTs) enable direct intercellular transfer of macromolecules, organelles, and pathogenic protein aggregates. While α-synuclein (α-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 α-Syn aggregates induce severe mitochondrial damage, leading to cytosolic release of mitochondrial DNA (mtDNA) and activation of the cGAS–STING–NF-κB–IRF3 pathway. This innate immune response drives actin cytoskeleton remodeling and the formation of TNT-like structures, promoting intercellular transfer of α-Syn from neurons to microglia. Additionally, neuronal cells transfer damaged mitochondria to microglia, where they undergo lysosome-mediated degradation. Neuron-to-microglia communication under α-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 α-Syn propagation, highlighting potential targets to modulate disease progression in Synucleinopathies.