PUBLICATION
Expression of a protein disulfide isomerase A3 variant associated with amyotrophic lateral sclerosis triggers disease features in mice
- Authors
- Sepulveda, M., Martinez-Traub, F., Ojeda, P., Perez, V., Ojeda, J., Mella, J., Diaz, R., Rozas, P., Mansilla-Jaramillo, M., Zuleta, A., Diaz, G., Kerr, B., Woehlbier, U., Henríquez, J.P., Medinas, D.B., Hetz, C.
- ID
- ZDB-PUB-250510-15
- Date
- 2025
- Source
- Neurobiology of disease : 106947106947 (Journal)
- Registered Authors
- Keywords
- Amyotrophic lateral sclerosis, Endoplasmic reticulum, Protein disulfide isomerase, Transgenic line
- MeSH Terms
-
- Mice
- Animals
- Humans
- Motor Neurons/metabolism
- Motor Neurons/pathology
- Spinal Cord/metabolism
- Spinal Cord/pathology
- Endoplasmic Reticulum Stress/genetics
- Amyotrophic Lateral Sclerosis*/genetics
- Amyotrophic Lateral Sclerosis*/metabolism
- Amyotrophic Lateral Sclerosis*/pathology
- Neuromuscular Junction/pathology
- Protein Disulfide-Isomerases*/genetics
- Protein Disulfide-Isomerases*/metabolism
- Disease Models, Animal
- Mice, Transgenic
- PubMed
- 40345258 Full text @ Neurobiol. Dis.
Citation
Sepulveda, M., Martinez-Traub, F., Ojeda, P., Perez, V., Ojeda, J., Mella, J., Diaz, R., Rozas, P., Mansilla-Jaramillo, M., Zuleta, A., Diaz, G., Kerr, B., Woehlbier, U., Henríquez, J.P., Medinas, D.B., Hetz, C. (2025) Expression of a protein disulfide isomerase A3 variant associated with amyotrophic lateral sclerosis triggers disease features in mice. Neurobiology of disease. :106947106947.
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motoneurons and compromised proteostasis. Dysfunction of the endoplasmic reticulum (ER) has been identified as a transversal pathogenic mechanism associated with motoneurons vulnerability in ALS. Protein disulfide isomerases (PDIs) are key enzymes catalyzing protein folding at the ER that are altered in the disease, involving biochemical and genetic perturbations. In ALS cases, we previously identified variants in the gene encoding PDIA3 (also known as Grp58 or ERp57), which were associated with altered neurite outgrowth in cell culture and abnormal motoneuron connectivity in zebrafish. Here, we report the generation of transgenic mice expressing the ALS-associated PDIA3Q481K variant. Moderate PDIA3Q481K overexpression resulted in altered motor capacity accompanied by decreased motoneuron number. The adverse effects of PDIA3Q481K were associated with induction of ER stress in the spinal cord and subtle morphological changes in neuromuscular junctions. Our results suggest that the PDIA3Q481K variant is likely pathogenic and its overexpression in mice recapitulate some ALS features, further supporting the concept that altered proteostasis due to PDI dysfunction may predispose an individual to develop the disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping