Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models - Archive ouverte HAL Access content directly
Journal Articles Science Translational Medicine Year : 2022

Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models

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Lucie Crouzier
Alberto Danese
Yuko Yasui
  • Function : Author
Elodie Richard
Simone Patergnani
Simon Couly
  • Function : Author
Camille Diez
  • Function : Author
Morgane Denus
  • Function : Author
Nicolas Cubedo
  • Function : Author
Mireille Rossel
Marc Thiry
Tsung-Ping Su
Paolo Pinton
  • Function : Author
Tangui Maurice
Benjamin Delprat

Abstract

The Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences; currently, no treatment is available. The disease is caused by mutations in the WSF1 gene, coding for the protein wolframin, an endoplasmic reticulum (ER) transmembrane protein involved in contacts between ER and mitochondria termed as mitochondria-associated ER membranes (MAMs). Inherited mutations usually reduce the protein’s stability, altering its homeostasis and ultimately reducing ER to mitochondria calcium ion transfer, leading to mitochondrial dysfunction and cell death. In this study, we found that activation of the sigma-1 receptor (S1R), an ER-resident protein involved in calcium ion transfer, could counteract the functional alterations of MAMs due to wolframin deficiency. The S1R agonist PRE-084 restored calcium ion transfer and mitochondrial respiration in vitro, corrected the associated increased autophagy and mitophagy, and was able to alleviate the behavioral symptoms observed in zebrafish and mouse models of the disease. Our findings provide a potential therapeutic strategy for treating Wolfram syndrome by efficiently boosting MAM function using the ligand-operated S1R chaperone. Moreover, such strategy might also be relevant for other degenerative and mitochondrial diseases involving MAM dysfunction.
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Dates and versions

hal-03870934 , version 1 (24-11-2022)

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Lucie Crouzier, Alberto Danese, Yuko Yasui, Elodie Richard, Jean-Charles Liévens, et al.. Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models. Science Translational Medicine, 2022, 14 (631), ⟨10.1126/scitranslmed.abh3763⟩. ⟨hal-03870934⟩

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