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

Abstract

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.

Intrinsic mechanisms for axon regeneration: insights from injured axons in Drosophila

“…Song et al suggested that Xbp-1 may be the target of Rtca during axonal regeneration since the enhanced regeneration observed in rtca mutants was largely abolished in Xbp-1, rtca double mutant flies. Such a role for Xbp-1 in axon regeneration would be consistent with other recent studies that have noted roles for ER stress pathways in regeneration [46,47]. However, the genetic data alone cannot exclude other potential (and yet unknown) targets of Rtca regulation.…”

Intrinsic mechanisms of neuronal axon regeneration

“…These RNA processing enzymes are involved in the unconventional mRNA splicing of X-box-binding protein 1 (XBP1), a stress sensor involved in the . XBP1 is required for regeneration and appears to have a role that is conserved in C. elegans, D. melanogaster and mice 89–91 . Another type of stress response, involving glucocorticoid release and increased expression of glucocorticoid receptors in sensory neurons, is also integral to the regenerative response after nerve injury 71 .…”

“…In addition to the previously highlighted transcription factors, several others — namely Myc proto-oncogene protein (MYC) 137 , hypoxia-inducible factor 1α (HIF1α) 138 , CREB1 (REFS 36,113 ), SOX11 (REFS 139–143 ), TP53 (REFS 46,144 ), SRF48,145 and XBP1 (REFS 90,91 ) — have been identified to have roles in axon regeneration (see TABLE 1 and REFS 146,147 ). As little is known about the mechanisms by which these transcription factors are activated after injury, their regulation during development or their downstream targets, they will not be further discussed in detail here.…”

“…A potential area of interest will be to determine whether the endoplasmic reticulum stress pathway and the miRNA biogenesis pathway, which are known to regulate each other, do so in the context of axon regeneration 184,185 . This is possible given that the endoplasmic reticulum stress response promotes regeneration of sensory neurons 91,186 and survival of RGCs 187 .…”

“…Following injury, calcium rapidly flows into the damaged axon and is actively propagated to the cell soma by voltage-gated calcium channels (VGCCs) and the release of calcium by internal stores in the endoplasmic reticulum (ER). The release of stored calcium also triggers cellular stress pathways in the axon, resulting in the splicing of X-box-binding protein 1 (XBP1) and its translocation to the nucleus 91 . The increase in calcium activates pro-regenerative pathways at the site of injury and in the cell soma.…”