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Peer-reviewedCC BYNature Communications

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

  • Ranabir Chakraborty1,2,3,4
  • Stephanie Maya1,3
  • Veronica Testa5,6,7,8
  • Jara Montero-Muñoz5,6,7,8
  • Takashi Nonaka9
  • Masato Hasegawa9
  • Antonella Consiglio5,6,7,8
  • Chiara Zurzolo10,11,3
11 affiliations
  1. 1Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Membrane Traffic and Pathogenesis, Paris, France
  2. 2Université Paris-Saclay, Gif-sur-Yvette, France
  3. 3Institut Pasteur, Université Paris Cité, CNRS UMR 369, Membrane Traffic and Pathogenesis, F-7505 Paris, France
  4. 4Université Paris-Saclay, 91190 Gif-sur-Yvette, France
  5. 5Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Barcelona, Spain
  6. 6Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
  7. 7Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital- IDIBELL, 08908 Hospitalet de Llobregat, Spain
  8. 8Institute of Biomedicine of the University of Barcelona (IBUB), Carrer Baldiri Reixac 15-21, Barcelona 08028, Spain
  9. 9Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
  10. 10Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Membrane Traffic and Pathogenesis, Paris, France. [email protected]
  11. 11Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{chakraborty2026αsynuclein,
  title = {{α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron–microglia communication}},
  author = {Ranabir Chakraborty and Stephanie Maya and Veronica Testa and Jara Montero-Muñoz and Takashi Nonaka and Masato Hasegawa and Antonella Consiglio and Chiara Zurzolo},
  journal = {Nature Communications},
  year = {2026},
  month = may,
  doi = {10.1038/s41467-026-73136-7},
  url = {https://doi.org/10.1038/s41467-026-73136-7},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron–microglia communication
AU  - Ranabir Chakraborty
AU  - Stephanie Maya
AU  - Veronica Testa
AU  - Jara Montero-Muñoz
AU  - Takashi Nonaka
AU  - Masato Hasegawa
AU  - Antonella Consiglio
AU  - Chiara Zurzolo
PY  - 2026
DA  - 2026/05/15
JO  - Nature Communications
DO  - 10.1038/s41467-026-73136-7
UR  - https://doi.org/10.1038/s41467-026-73136-7
AB  - 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.
SN  - 2041-1723
ER  -