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ALS‐linked protein disulfide isomerase variants cause motor dysfunction |
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| Authors: | Ute Woehlbier Alicia Colombo Mirva J Saaranen Viviana Pérez Jorge Ojeda Fernando J Bustos Catherine I Andreu Mauricio Torres Vicente Valenzuela Danilo B Medinas Pablo Rozas Rene L Vidal Rodrigo Lopez‐Gonzalez Johnny Salameh Sara Fernandez‐Collemann Natalia Muñoz Soledad Matus Ricardo Armisen Alfredo Sagredo Karina Palma Thergiory Irrazabal Sandra Almeida Paloma Gonzalez‐Perez Mario Campero Fen‐Biao Gao Pablo Henny Brigitte van Zundert Lloyd W Ruddock Miguel L Concha Juan P Henriquez Robert H Brown Claudio Hetz |
| Affiliation: | 1. Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile;2. Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile;3. Center for Genomics and Bioinformatics, Universidad Mayor, Santiago, Chile;4. Program of Anatomy and Developmental Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile;5. Department of Pathological Anatomy, Hospital Clínico, University of Chile, Santiago, Chile;6. Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland;7. Department of Cell Biology, Faculty of Biological Sciences, Millennium Nucleus of Regenerative Biology, Center for Advanced Microscopy (CMA Bio‐Bio), Universidad de Concepción, Concepción, Chile;8. Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile;9. Center for Geroscience, Brain Health and Metabolism, Santiago, Chile;10. Neurounion Biomedical Foundation, CENPAR, Santiago, Chile;11. Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA;12. Department of Anatomy, Medical School, Universidad Católica de Chile, Santiago, Chile;13. Department of Neurology and Neurosurgery, Faculty of Medicine, University of Chile, Santiago, Chile;14. Faculty of Medicine, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile;15. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA |
| 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. |
| Keywords: | amyotrophic lateral sclerosis ERp57 PDIA1 protein disulfide isomerase |