Activation of the unfolded protein response promotes axonal regeneration after peripheral nerve injury
Author
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Oñate, Martiza
Author
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Catenaccio, Alejandra
Author
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Martínez, Gabriela
Author
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Armentano, Donna
Author
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Parsons, Geoffrey
Author
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Kerr, Bredford
Author
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Hetz Flores, Claudio
Author
dc.contributor.author
Court, Felipe
Admission date
dc.date.accessioned
2016-06-21T22:32:34Z
Available date
dc.date.available
2016-06-21T22:32:34Z
Publication date
dc.date.issued
2016
Cita de ítem
dc.identifier.citation
Scientific Reports | 6:21709 | 2016
en_US
Identifier
dc.identifier.issn
2045-2322
Identifier
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DOI: 10.1038/srep21709
Identifier
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https://repositorio.uchile.cl/handle/2250/139067
General note
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Artículo de publicación ISI
en_US
Abstract
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Although protein-folding stress at the endoplasmic reticulum (ER) is emerging as a driver of neuronal dysfunction in models of spinal cord injury and neurodegeneration, the contribution of this pathway to peripheral nerve damage remains poorly explored. Here we targeted the unfolded protein response (UPR), an adaptive reaction against ER stress, in mouse models of sciatic nerve injury and found that ablation of the transcription factor XBP1, but not ATF4, significantly delay locomotor recovery. XBP1 deficiency led to decreased macrophage recruitment, a reduction in myelin removal and axonal regeneration. Conversely, overexpression of XBP1s in the nervous system in transgenic mice enhanced locomotor recovery after sciatic nerve crush, associated to an improvement in key pro-regenerative events. To assess the therapeutic potential of UPR manipulation to axonal regeneration, we locally delivered XBP1s or an shRNA targeting this transcription factor to sensory neurons of the dorsal root ganglia using a gene therapy approach and found an enhancement or reduction of axonal regeneration in vivo, respectively. Our results demonstrate a functional role of specific components of the ER proteostasis network in the cellular changes associated to regeneration and functional recovery after peripheral nerve injury.
en_US
Patrocinador
dc.description.sponsorship
Millennium Nucleus
P-07-011-F
FONDECYT
1110987
1140549
3150637
Ring Initiative
ACT1109
Millennium Institute
P09-015-F
Frick Foundation
Michael J Fox Foundation for Parkinson's Research
COPEC-UC Foundation
CONICYT-USA
2013-0003
ECOS-CONICYT
C13S02
Muscular Dystrophy Association
382453
ALS Therapy Alliance
2014-F-059
Office of Naval Research-Global (ONR-G)
N62909-16-1-2003
ALSRP Therapeutic Idea Award
AL150111
Centers of Excellence Basal Financing Program of CONICYT
CONICYT
FONDAP-15150012