α-突触核蛋白聚集物诱导线粒体损伤，触发先天免疫，驱动神经元-小胶质细胞通讯
α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.
摘要(中文译文)
隧道纳米管（TNTs）能够介导大分子、细胞器及致病性蛋白聚集体的直接细胞间转移。已知α-突触核蛋白（α-Syn）聚集体可促进TNT形成，但其潜在机制尚不明确。本研究利用人神经元和微胶质细胞系，以及iPSC来源的多巴胺能神经元和微胶质细胞，发现α-Syn聚集体可诱导严重的线粒体损伤，导致线粒体DNA（mtDNA）释放至胞质并激活cGAS-STING-NF-κB-IRF3通路。该先天免疫反应驱动肌动蛋白细胞骨架重塑及TNT样结构的形成，促进α-Syn从神经元向微胶质细胞的细胞间转移。此外，神经元细胞将受损线粒体转移至微胶质细胞，后者通过溶酶体介导的降解途径将其清除。在α-Syn诱导的应激条件下，神经元向微胶质细胞的通讯还可触发微胶质细胞的旁观者炎症反应，提示神经免疫激活。本研究揭示了线粒体损伤和STING介导的炎症是TNT形成及α-Syn传播的关键驱动因素，为调控突触核蛋白病的疾病进展提供了潜在靶点。
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.
如何引用
AMA
Ranabir Chakraborty, Stephanie Maya, Veronica Testa, Jara Montero-Muñoz, Takashi Nonaka, Masato Hasegawa, et al. α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.. Nature communications. 2026; doi:10.1038/s41467-026-73136-7.
APA
Ranabir Chakraborty, Stephanie Maya, Veronica Testa, Jara Montero-Muñoz, Takashi Nonaka, Masato Hasegawa, et al (2026). α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.. Nature communications. https://doi.org/10.1038/s41467-026-73136-7
GB/T 7714
Ranabir Chakraborty, Stephanie Maya, Veronica Testa, Jara Montero-Muñoz, Takashi Nonaka, Masato Hasegawa, et al. α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.[J]. Nature communications, 2026 doi:10.1038/s41467-026-73136-7.
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