Ligand-mediated Galectin-1 endocytosis prevents intraneural H2O2 production promoting F-actin dynamics reactivation and axonal re-growth
Author
dc.contributor.author
Quinta, Héctor R.
Author
dc.contributor.author
Wilson, Carlos
Author
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Blidner, Ada G.
Author
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González Billault, Christian
Author
dc.contributor.author
Pasquini, Laura A.
Author
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Rabinovich, Gabriel A.
Author
dc.contributor.author
Pasquini, Juana M.
Admission date
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2017-03-01T20:46:32Z
Available date
dc.date.available
2017-03-01T20:46:32Z
Publication date
dc.date.issued
2016
Cita de ítem
dc.identifier.citation
Experimental Neurology. Volumen: 283 Páginas: 165-178 Subdivisión: A
es_ES
Identifier
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10.1016/j.expneurol.2016.06.009
Identifier
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https://repositorio.uchile.cl/handle/2250/142901
Abstract
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Axonal growth cone collapse following spinal cord injury (SCI) is promoted by semaphorin3A (Sema3A) signaling via PlexinA4 surface receptor. This interaction triggers intracellular signaling events leading to increased hydrogen peroxide levels which in turn promote filamentous actin (F-actin) destabilization and subsequent inhibition of axonal re-growth. In the current study, we demonstrated that treatment with galectin-1 (Gal-1), in its dimeric form, promotes a decrease in hydrogen peroxide (H2O2) levels and F-actin repolimerization in the growth cone and in the filopodium of neuron surfaces. This effect was dependent on the carbohydrate recognition activity of Gal-1, as it was prevented using a Gal-1 mutant lacking carbohydrate-binding activity. Furthermore, Gal-1 promoted its own active ligand-mediated endocytosis together with the PlexinA4 receptor, through mechanisms involving complex branched N-glycans. In summary, our results suggest that Gal-1, mainly in its dimeric form, promotes re -activation of actin cytoskeleton dynamics via internalization of the PlexinA4/Gal-1 complex. This mechanism could explain, at least in part, critical events in axonal regeneration including the full axonal re-growth process, de novo formation of synapse clustering, axonal re-myelination and functional recovery of coordinated locomotor activities in an in vivo acute and chronic SCI model.
Significance statement: Axonal regeneration is a response of injured nerve cells critical for nerve repair in human spinal cord injury. Understanding the molecular mechanisms controlling nerve repair by Galectin-1, may be critical for therapeutic intervention. Our results show that Galectin-1; in its dimeric form, interferes with hydrogen peroxide production triggered by Semaphorin3A. The high levels of this reactive oxygen species (ROS) seem to be the main factor preventing axonal regeneration due to promotion of actin depolymerization at the axonal growth cone. Thus, Galectin-1 administration emerges as a novel therapeutic modality for promoting nerve repair and preventing axonal loss. (C) 2016 Elsevier Inc. All rights reserved.