ALS‐linked protein disulfide isomerase variants cause motor dysfunction
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 11, 2016
- Source ID
- 10.15252/embj.201592224
Entities
People
- Alfredo Sagredo
- Alicia Colombo
- Brigitte Van Zundert
- Catherine I Andreu
- Claudio Hetz
- Danilo B. Medinas
- Fen‐biao Gao
- Fernando J Bustos
- Johnny Salameh
- Jorge Ojeda
- Juan P. Henríquez
- Karina Palma
- Lloyd W Ruddock
- Mario Campero
- Mauricio Torres
- Miguel L Concha
- Mirva J Saaranen
- Natalia Muñoz
- Pablo Henny
- Pablo Rozas
- Paloma Gonzalez‐perez
- Rene L. Vidal
- Ricardo Armisen
- Robert H. Brown
- Rodrigo Lopez‐gonzalez
- Sandra Almeida
- Sara Fernandez‐collemann
- Soledad Matus
- Thergiory Irrazabal
- Ute Woehlbier
- Vicente Valenzuela
- Viviana Pérez
Organizations
- ALS Therapy Alliance
- Andrés Bello University
- CONICYT
- Colorado Power Electronics Center, University of Colorado Boulder
- Harvard T.H. Chan School of Public Health
- Howard Hughes Medical Institute
- Muscular Dystrophy Association
- National Fund for Scientific and Technological Development
- National Institutes of Health
- Neurounion Biomedical Foundation
- Office of Naval Research Global
- Pontifical Catholic University of Chile
- The Michael J. Fox Foundation
- Universidad del Desarrollo
- University of Chile
- University of Massachusetts Medical School
- University of Oulu