1. Academic Validation
  2. Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway

Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway

  • Neuropathol Appl Neurobiol. 2022 Aug;48(5):e12816. doi: 10.1111/nan.12816.
Domenico D'Amico 1 Olivier Biondi 1 Camille Januel 2 Cynthia Bezier 1 3 Delphine Sapaly 1 Zoé Clerc 1 Mirella El Khoury 1 Venkat Krishnan Sundaram 1 Léo Houdebine 1 Thibaut Josse 4 Bruno Della Gaspera 1 Cécile Martinat 2 Charbel Massaad 1 Laure Weill 1 Frédéric Charbonnier 1
Affiliations

Affiliations

  • 1 Université Paris cité and Inserm UMR_S1124, Paris, France.
  • 2 Université d'Evry-Val-d'Essonne and Inserm UMR 861, I-STEM, AFM, Corbeil-Essonne, France.
  • 3 Biophytis, Sorbonne Université, Paris, France.
  • 4 Université de Tour and CNRS UMR 7261, Institut de Recherche sur la Biologie de l'Insecte, Tours, France.
Abstract

Aim: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by survival of motor neuron (SMN) deficiency that induces motor neuron (MN) degeneration and severe muscular atrophy. Gene therapies that increase SMN have proven their efficacy but not for all patients. Here, we explored the unfolded protein response (UPR) status in SMA pathology and explored whether UPR modulation could be beneficial for SMA patients.

Methods: We analysed the expression and activation of key UPR proteins by RT-qPCR and by western blots in SMA patient iPSC-derived MNs and one SMA cell line in which SMN expression was re-established (rescue). We complemented this approach by using myoblast and fibroblast SMA patient cells and SMA mouse models of varying severities. Finally, we tested in vitro and in vivo the effect of IRE1α/XBP1 pathway restoration on SMN expression and subsequent neuroprotection.

Results: We report that the IRE1α/XBP1 branch of the unfolded protein response is disrupted in SMA, with a depletion of XBP1s irrespective of IRE1α activation pattern. The overexpression of XBP1s in SMA fibroblasts proved to transcriptionally enhance SMN expression. Importantly, rebalancing XBP1s expression in severe SMA-like mice, induced SMN expression and spinal MN protection.

Conclusions: We have identified XBP1s depletion as a contributing factor in SMA pathogenesis, and the modulation of this transcription factor proves to be a plausible therapeutic avenue in the context of pharmacological interventions for patients.

Keywords

IRE1α; SMN; XBP1; neuroprotection; spinal muscular atrophy; unfolded protein response.

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