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.
Highlights
IntroductionIRE1α catalyzes the unconventional splicing of the mRNA encoding for Xbp[1], eliminating an intron of 26 nucleotides
At 21 dpi, when Wallerian degeneration is complete and remyelination of new fibers is under way, BiP protein levels return to basal values similar to the uninjured condition (Fig. 1C)
Analysis of direct markers of the PERK pathway revealed no induction in the mRNA levels of the proapoptotic ATF4 effectors Chop and Gadd[34] (Fig. 1G and Supplementary Fig. S1A and B)
Summary
IRE1α catalyzes the unconventional splicing of the mRNA encoding for Xbp[1], eliminating an intron of 26 nucleotides This processing event shifts the coding reading frame of the mRNA, leading to the production of an active transcription factor termed XBP1s9. The upregulation of ER stress markers has been reported in neurons after mechanical damage to the PNS17–20, the functional role of the UPR in axonal regeneration and locomotor recovery after peripheral nerve injury remains to be determined. We report the activation of an ER stress reaction in the injured nerve, and show that genetic ablation of Xbp[1], but not Atf[4], results in a significant delay of locomotor recovery after damage, associated to a decrease in macrophage infiltration, reduced myelin removal and lower density of regenerated axons. Our results identify selective components of the proteostasis network as possible therapeutic targets to increase locomotor recovery after damage to the nervous system
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
