Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes
| Autor: | Daniela Triolo, Vittorio Martinelli, Emanuela Colombo, Claudia Bassani, Jia Newcombe, Carla Taveggia, Evelien Fredrickx, Marco Di Dario, Giancarlo Comi, Francesco Bedogni, Isabella Fermo, Cinthia Farina, Angelo Quattrini, Giorgia Dina |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Encephalomyelitis
Autoimmune Experimental Multiple Sclerosis Tropomyosin receptor kinase B Ligands Cicatrix Cuprizone Transactivation medicine Animals Humans Receptor trkB Nerve Growth Factors Myelin Sheath Neuroinflammation Inflammation Mice Knockout Multidisciplinary biology Chemistry musculoskeletal neural and ocular physiology Multiple sclerosis Membrane Transport Proteins Biological Transport medicine.disease White Matter Oligodendrocyte Up-Regulation Cell biology Disease Models Animal medicine.anatomical_structure nervous system Astrocytes Chronic Disease Neurotrophin binding Commentary biology.protein Copper Neurotrophin Astrocyte |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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