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Tytuł pozycji:

Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes.

Tytuł:
Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes.
Autorzy:
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
Cinthia Farina, Cinthia
Temat:
MULTIPLE sclerosis
DEMYELINATION
NEUROTROPHIN receptors
COPPER
ASTROCYTES
COMMERCIAL products
CURCUMIN
Źródło:
Proceedings of the National Academy of Sciences of the United States of America; 7/6/2021, Vol. 118 Issue 27, p1-10, 10p
Czasopismo naukowe
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. [ABSTRACT FROM AUTHOR]
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