Activation of the unfolded protein response promotes axonal regeneration after peripheral nerve injury

Artículo de publicación ISIAlthough 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.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-1515001