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

Scientific Reports
Maritza OñateFelipe A Court

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 associa...Continue Reading

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Citations

Feb 22, 2017·Traffic·Víctor Hugo CornejoAndrés Couve
May 2, 2016·Brain Research·Vicente ValenzuelaClaudio Hetz
Apr 28, 2016·Brain Research·Vicente ValenzuelaFelipe A Court
Feb 25, 2017·Current Opinion in Genetics & Development·Yan Hao, Catherine Collins
Jul 22, 2017·Nature Reviews. Neurology·Claudio Hetz, Smita Saxena
Nov 18, 2017·The FEBS Journal·Yannis Gerakis, Claudio Hetz
Nov 10, 2017·Cell Death & Disease·Alejandra CatenaccioFelipe A Court
Jun 4, 2018·Human Molecular Genetics·David GonzalezEnrique Brandan
Jun 24, 2017·Journal of Neurochemistry·Mark HallidayGiovanna R Mallucci
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Apr 25, 2017·Aging Cell·Gabriela MartínezClaudio Hetz
Sep 21, 2017·Frontiers in Neuroscience·Natalia SalvadoresFelipe A Court
Feb 3, 2018·International Journal of Molecular Medicine·Weiping Zhang, Jianming Xu
Apr 25, 2019·Nature Communications·Xia RongHengquan Yang
Mar 28, 2017·Acta Neuropathologica·Claudia Duran-AniotzClaudio Hetz
Apr 19, 2018·Nature Reviews. Neuroscience·Marcus Mahar, Valeria Cavalli
Jul 23, 2020·Molecular Neurobiology·Dominique LemaitreFelipe A Court
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Feb 6, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·René L VidalClaudio Hetz
Apr 10, 2020·Progress in Retinal and Eye Research·Marina S GorbatyukOleg S Gorbatyuk
Jun 28, 2018·Trends in Neurosciences·Gabriela MartínezClaudio Hetz
May 4, 2020·Brain Research·Terika P SmithJeffery L Twiss
Mar 7, 2021·International Journal of Molecular Sciences·Veselina PetrovaRichard Eva
May 8, 2018·Molecular Therapy : the Journal of the American Society of Gene Therapy·Vicente ValenzuelaClaudio Hetz
Jul 3, 2021·International Journal of Molecular Sciences·Núria Gaja-CapdevilaMireia Herrando-Grabulosa
Jul 9, 2020·Neuron·Xiao LiuMarc Hammarlund

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Methods Mentioned

BETA
protein folding
PCR
transgenic

Software Mentioned

GraphPad Prims
ImageJ

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