Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes

Colombo, Emanuela, Triolo, Daniela, Bassani, Claudia, Bedogni, Francesco, Di Dario, Marco, Dina, Giorgia, Fredrickx, Evelien, Fermo, Isabella, Martinelli, Vittorio, Newcombe, Jia, Taveggia, Carla, Quattrini, Angelo, Comi, Giancarlo and Farina, Cinthia 2021. Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes. Proceedings of the National Academy of Sciences 118 (27) , e2025804118. 10.1073/pnas.2025804118

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of First Compliant Deposit:	7 December 2021
Date of Acceptance:	21 May 2021
Last Modified:	08 Nov 2023 00:58
URI:	https://orca.cardiff.ac.uk/id/eprint/145120

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