Affordable Access

deepdyve-link
Publisher Website

Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis.

Authors
  • Couly, Simon1
  • Khalil, Bilal2
  • Viguier, Véronique3
  • Roussel, Julien4
  • Maurice, Tangui1
  • Liévens, Jean-Charles1
  • 1 MMDN, Univ Montpellier, INSERM, EPHE, F-34095 Montpellier, France. , (France)
  • 2 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • 3 MEA, Univ Montpellier, F-34095 Montpellier, France. , (France)
  • 4 IBMM, Univ Montpellier, CNRS, F-34095 Montpellier, France. , (France)
Type
Published Article
Journal
Human Molecular Genetics
Publisher
Oxford University Press
Publication Date
Mar 13, 2020
Volume
29
Issue
4
Pages
529–540
Identifiers
DOI: 10.1093/hmg/ddz267
PMID: 31696229
Source
Medline
Language
English
License
Unknown

Abstract

Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that not only regulates mitochondrial respiration but also controls cellular defense against ER and oxidative stress. This makes S1R a potential therapeutic target in amyotrophic lateral sclerosis (ALS). Especially, as a missense mutation E102Q in S1R has been reported in few familial ALS cases. However, the pathogenicity of S1RE102Q and the beneficial impact of S1R in the ALS context remain to be demonstrated in vivo. To address this, we generated transgenic Drosophila that expresses human wild-type S1R or S1RE102Q. Expression of mutant S1R in fly neurons induces abnormal eye morphology and locomotor defects in a dose-dependent manner. This was accompanied by abnormal mitochondrial fragmentation, reduced adenosine triphosphate (ATP) levels and a higher fatigability at the neuromuscular junction during high energy demand. Overexpressing IP3 receptor or glucose transporter mitigates the S1RE102Q-induced eye phenotype, further highlighting the role of calcium and energy metabolism in its toxicity. More importantly, we showed that wild-type S1R rescues locomotor activity and ATP levels of flies expressing the key ALS protein, TDP43. Moreover, overexpressing wild-type S1R enhances resistance of flies to oxidative stress. Therefore, our data provide the first genetic evidence that mutant S1R recapitulates ALS pathology in vivo while increasing S1R confers neuroprotection against TDP43 toxicity. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

Report this publication

Statistics

Seen <100 times