星形胶质细胞
原肌球蛋白受体激酶B
少突胶质细胞
神经炎症
细胞生物学
神经营养因子
髓鞘
多发性硬化
神经科学
中枢神经系统
生物
化学
免疫学
受体
炎症
生物化学
作者
Emanuela Colombo,Daniela Triolo,Claudia Bassani,Francesco Bedogni,Marco Di Dario,Giorgia Dina,Evelien Fredrickx,Isabella Fermo,Vittorio Martinelli,Jia Newcombe,Carla Taveggia,Angelo Quattrini,Gıancarlo Comı,Cinthia Farina
标识
DOI:10.1073/pnas.2025804118
摘要
Demyelination is a key pathogenic feature of multiple sclerosis (MS). Here, we evaluated the astrocyte contribution to myelin loss and focused on the neurotrophin receptor TrkB, whose up-regulation on the astrocyte finely demarcated chronic demyelinated areas in MS and was paralleled by neurotrophin loss. Mice lacking astrocyte TrkB were resistant to demyelination induced by autoimmune or toxic insults, demonstrating that TrkB signaling in astrocytes fostered oligodendrocyte damage. In vitro and ex vivo approaches highlighted that astrocyte TrkB supported scar formation and glia proliferation even in the absence of neurotrophin binding, indicating TrkB transactivation in response to inflammatory or toxic mediators. Notably, our neuropathological studies demonstrated copper dysregulation in MS and model lesions and TrkB-dependent expression of copper transporter (CTR1) on glia cells during neuroinflammation. In vitro experiments evidenced that TrkB was critical for the generation of glial intracellular calcium flux and CTR1 up-regulation induced by stimuli distinct from neurotrophins. These events led to copper uptake and release by the astrocyte, and in turn resulted in oligodendrocyte loss. Collectively, these data demonstrate a pathogenic demyelination mechanism via the astrocyte release of copper and open up the possibility of restoring copper homeostasis in the white matter as a therapeutic target in MS.
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