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

• Published in: Scientific reports Vol. 6; no. 1; p. 21709
• Main Authors: Oñate, Maritza, Catenaccio, Alejandra, Martínez, Gabriela, Armentano, Donna, Parsons, Geoffrey, Kerr, Bredford, Hetz, Claudio, Court, Felipe A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 24.02.2016
• Subjects: Activating Transcription Factor 4 - metabolism; Animal models; Animals; Axon guidance; Axons - physiology; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Dorsal root ganglia; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Gene Expression; Gene therapy; Locomotion; Macrophages; Macrophages - physiology; Mice, Inbred C57BL; Mice, Knockout; Myelin; Nerve Regeneration; Nervous system; Neurodegeneration; Peripheral Nerve Injuries - physiopathology; Peripheral nerves; Protein folding; Proteins; Recovery of Function; Regeneration; Rodents; Sciatic nerve; Sciatic Nerve - injuries; Sciatic Nerve - metabolism; Sciatic Nerve - physiopathology; Sensory neurons; Spinal cord injuries; Transcription factors; Transgenic mice; Unfolded Protein Response; X-Box Binding Protein 1 - genetics; X-Box Binding Protein 1 - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep21709

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.