a-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.
Por:
Chakraborty R, Maya S, Testa V, Montero-Muñoz J, Nonaka T, Hasegawa M, Consiglio A and Zurzolo C
Publicada:
15 may 2026
Ahead of Print:
15 may 2026
Resumen:
Tunneling nanotubes (TNTs) enable direct intercellular transfer of macromolecules, organelles, and pathogenic protein aggregates. While a-synuclein (a-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 a-Syn aggregates induce severe mitochondrial damage, leading to cytosolic release of mitochondrial DNA (mtDNA) and activation of the cGAS-STING-NF-?B-IRF3 pathway. This innate immune response drives actin cytoskeleton remodeling and the formation of TNT-like structures, promoting intercellular transfer of a-Syn from neurons to microglia. Additionally, neuronal cells transfer damaged mitochondria to microglia, where they undergo lysosome-mediated degradation. Neuron-to-microglia communication under a-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 a-Syn propagation, highlighting potential targets to modulate disease progression in Synucleinopathies.
Filiaciones:
Chakraborty R:
Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Membrane Traffic and Pathogenesis, Paris, France
Université Paris-Saclay, Gif-sur-Yvette, France
Maya S:
Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Membrane Traffic and Pathogenesis, Paris, France
Testa V:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Barcelona, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Montero-Muñoz J:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Barcelona, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Nonaka T:
Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Hasegawa M:
Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Consiglio A:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Barcelona, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Zurzolo C:
Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Membrane Traffic and Pathogenesis, Paris, France
Open Access
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