PUBLICATION
ALS-linked protein disulfide isomerase variants cause motor dysfunction
- Authors
- Woehlbier, U., Colombo, A., Saaranen, M.J., Pérez, V., Ojeda, J., Bustos, F.J., Andreu, C.I., Torres, M., Valenzuela, V., Medinas, D.B., Rozas, P., Vidal, R.L., Lopez-Gonzalez, R., Salameh, J., Fernandez-Collemann, S., Muñoz, N., Matus, S., Armisen, R., Sagredo, A., Palma, K., Irrazabal, T., Almeida, S., Gonzalez-Perez, P., Campero, M., Gao, F.B., Henny, P., van Zundert, B., Ruddock, L.W., Concha, M.L., Henriquez, J.P., Brown, R.H., Hetz, C.
- ID
- ZDB-PUB-160213-6
- Date
- 2016
- Source
- The EMBO journal 35(8): 845-65 (Journal)
- Registered Authors
- Concha, Miguel
- Keywords
- ERp57, PDIA1, amyotrophic lateral sclerosis, protein disulfide isomerase
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis/genetics*
- Amyotrophic Lateral Sclerosis/pathology
- Animals
- Animals, Genetically Modified
- Electromyography
- Embryo, Nonmammalian
- Endoplasmic Reticulum Stress/genetics
- Humans
- Mice, Knockout
- Motor Neurons/pathology*
- Mutation
- Neurites/pathology
- Procollagen-Proline Dioxygenase/genetics*
- Procollagen-Proline Dioxygenase/metabolism
- Protein Disulfide-Isomerases/genetics*
- Protein Disulfide-Isomerases/metabolism
- Zebrafish/embryology
- Zebrafish/genetics
- PubMed
- 26869642 Full text @ EMBO J.
Citation
Woehlbier, U., Colombo, A., Saaranen, M.J., Pérez, V., Ojeda, J., Bustos, F.J., Andreu, C.I., Torres, M., Valenzuela, V., Medinas, D.B., Rozas, P., Vidal, R.L., Lopez-Gonzalez, R., Salameh, J., Fernandez-Collemann, S., Muñoz, N., Matus, S., Armisen, R., Sagredo, A., Palma, K., Irrazabal, T., Almeida, S., Gonzalez-Perez, P., Campero, M., Gao, F.B., Henny, P., van Zundert, B., Ruddock, L.W., Concha, M.L., Henriquez, J.P., Brown, R.H., Hetz, C. (2016) ALS-linked protein disulfide isomerase variants cause motor dysfunction. The EMBO journal. 35(8):845-65.
Abstract
Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) are ER foldases identified as possible ALS biomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized four ALS-linked mutations recently identified in two major PDI genes, PDIA1 and PDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of these PDI variants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutant PDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of these PDI mutants. Finally, targeting ERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifies ER proteostasis imbalance as a risk factor for ALS, driving initial stages of the disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping