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Exp Neurol. 2016 Sep;283(Pt A):165-78. doi: 10.1016/j.expneurol.2016.06.009. Epub 2016 Jun 11.

Ligand-mediated Galectin-1 endocytosis prevents intraneural H2O2 production promoting F-actin dynamics reactivation and axonal re-growth.

Author information

1
Departamento de Química Biológica, Instituto de Química y Físico Química Biológica, Universidad de Buenos Aires, Buenos Aires C1113AAD, Argentina.
2
Laboratory of Cell and Neuronal Dymanics, Faculty of Sciences, Universidad de Chile. Center for Geroscience, Brain Health and Metabolism, Santiago, Chile. The Buck Institute for Research on Aging, Novato, USA.
3
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Buenos Aires C1428, Argentina.
4
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Buenos Aires C1428, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428, Argentina.
5
Departamento de Química Biológica, Instituto de Química y Físico Química Biológica, Universidad de Buenos Aires, Buenos Aires C1113AAD, Argentina. Electronic address: jpasquin@qb.ffyb.uba.ar.

Abstract

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.

KEYWORDS:

Axonal growth; Filamentous actin; Galectin-1; Hydrogen peroxide; PlexinA4; Semaphorin3A; Spinal cord injury

PMID:
27296316
DOI:
10.1016/j.expneurol.2016.06.009
[Indexed for MEDLINE]

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