PUBLICATION
Sigma-1 receptor agonist PRE-084 confers protection against TAR DNA-binding protein-43 toxicity through NRF2 signalling
- Authors
- Lasbleiz, C., Peyrel, A., Tarot, P., Sarniguet, J., Crouzier, L., Cubedo, N., Delprat, B., Rossel, M., Maurice, T., Liévens, J.C.
- ID
- ZDB-PUB-221129-9
- Date
- 2022
- Source
- Redox Biology 58: 102542102542 (Journal)
- Registered Authors
- Cubedo, Nicolas, Lievens, Jean-Charles, Rossel, Mireille
- Keywords
- none
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis*/genetics
- Animals
- Antioxidants/therapeutic use
- DNA-Binding Proteins/genetics
- Endoplasmic Reticulum Stress
- NF-E2-Related Factor 2/genetics
- NF-E2-Related Factor 2/metabolism
- Neurodegenerative Diseases*
- Zebrafish/metabolism
- PubMed
- 36442393 Full text @ Redox Biol.
Citation
Lasbleiz, C., Peyrel, A., Tarot, P., Sarniguet, J., Crouzier, L., Cubedo, N., Delprat, B., Rossel, M., Maurice, T., Liévens, J.C. (2022) Sigma-1 receptor agonist PRE-084 confers protection against TAR DNA-binding protein-43 toxicity through NRF2 signalling. Redox Biology. 58:102542102542.
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons. As a consequence, ALS patients display a locomotor disorder related to muscle weakness and progressive paralysis. Pathological mechanisms that participate in ALS involve deficient unfolded protein response, mitochondrial dysfunction and oxidative stress, among others. Finding a therapeutic target to break the vicious circle is particularly challenging. Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that may be one of those targets. We here address and decipher the efficiency of S1R activation on a key ALS gene, TDP43, in zebrafish vertebrate model. While expression of mutant TDP43 (TDP43G348C) led to locomotor defects, treatment with the reference S1R agonist PRE-084 rescued motor performances in a zebrafish model. Treatment with the agonist ameliorated maximal mitochondrial respiration in the TDP43 context. We observed that TDP43G348C exacerbated ER stress induced by tunicamycin, resulting in increased levels of ER stress chaperone BiP and pro-apoptotic factor CHOP. Importantly, PRE-084 treatment in the same condition further heightened BiP levels but also EIF2α/ATF4 and NRF2 signalling cascades, both known to promote antioxidant protection during ER stress. Moreover, we showed that increasing NRF2 levels directly or by sulforaphane treatment rescued locomotor defects of TDP43G348C zebrafish. For the first time, we here provide the proof of concept that PRE-084 prevents mutant TDP43 toxicity by boosting ER stress response and antioxidant cascade through NRF2 signalling.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping