PUBLICATION
Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models
- Authors
- Abgueguen, E., Tortarolo, M., Rouviere, L., Marcuzzo, S., Camporeale, L., Henriques, A., Pasetto, L., Culley, G.R., Bonetto, V., Marian, A., Lejeune, B.L., Visbecq, A., Lauria, G., Kabashi, E., Callizot, N., Bendotti, C., Miniou, P.Y.
- ID
- ZDB-PUB-250703-14
- Date
- 2025
- Source
- Life science alliance 8: (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Disease Models, Animal
- Unfolded Protein Response/drug effects
- Animals
- Motor Neurons*/drug effects
- Motor Neurons*/metabolism
- Spinal Cord/metabolism
- Humans
- Endoplasmic Reticulum Stress/drug effects
- Mitochondria/drug effects
- Mitochondria/metabolism
- Apoptosis/drug effects
- Amyotrophic Lateral Sclerosis*/drug therapy
- Amyotrophic Lateral Sclerosis*/metabolism
- Amyotrophic Lateral Sclerosis*/pathology
- Mice
- Cytoplasm/metabolism
- Zebrafish
- DNA-Binding Proteins*/genetics
- DNA-Binding Proteins*/metabolism
- Reactive Oxygen Species/metabolism
- Oxidative Stress/drug effects
- Cell Survival/drug effects
- Mice, Transgenic
- PubMed
- 40602832 Full text @ Life Sci Alliance
Citation
Abgueguen, E., Tortarolo, M., Rouviere, L., Marcuzzo, S., Camporeale, L., Henriques, A., Pasetto, L., Culley, G.R., Bonetto, V., Marian, A., Lejeune, B.L., Visbecq, A., Lauria, G., Kabashi, E., Callizot, N., Bendotti, C., Miniou, P.Y. (2025) Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models. Life science alliance. 8:.
Abstract
A pathological hallmark of ALS is the abnormal accumulation of misfolded proteins (e.g., TDP-43) and enlarged endoplasmic reticulum (ER), indicating ER stress. To resolve this stress, cells initiate the Unfolded Protein Response (UPR). However, unresolved stress leads to apoptosis. In ALS, UPR activation fails to resolve proteostasis impairment. UPR activation modulators, among them Sephin1, reduce protein aggregates and improve motor neuron survival in ALS models. We demonstrate that following glutamate intoxication, Sephin1 increases motor neuron survival by reducing mitochondria ROS production and extranuclear TDP-43. Sephin1 reduces abnormal splicing because of TDP-43 nuclear loss of function following oxidative stress. In SOD1G93A mice, Sephin1 treatment decreases TDP-43 in triton-insoluble fraction, improving motor neuron survival in spinal cord. Sephin1 improves motor neurons survival, motor function and survival of mutated TDP-43 transgenic zebrafish. Sephin1 improves motor neuron survival in ALS models by reducing TDP-43 cytoplasmic mislocalization and its toxicity. These findings open new therapeutic opportunities for Sephin1 in neurodegenerative pathologies with TDP-43 proteinopathy, including ALS.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping