title: 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) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized fourALS-linked mutations recently identified in two majorPDIgenes,PDIA1 andPDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of thesePDIvariants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutantPDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of thesePDImutants. Finally, targetingERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifiesERproteostasis imbalance as a risk factor forALS, driving initial stages of the disease.
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile Center for Genomics and Bioinformatics, Universidad Mayor, Santiago, Chile.
authors: Ute
authors: U
authors: Woehlbier
authors: Program of Anatomy and Developmental Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile Department of Pathological Anatomy, Hospital Clínico, University of Chile, Santiago, Chile.
authors: Alicia
authors: A
authors: Colombo
authors: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors: Mirva J
authors: MJ
authors: Saaranen
authors: 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.
authors: Viviana
authors: V
authors: Pérez
authors: 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.
authors: Jorge
authors: J
authors: Ojeda
authors: Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile.
authors: Fernando J
authors: FJ
authors: Bustos
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors: Catherine I
authors: CI
authors: Andreu
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors: Mauricio
authors: M
authors: Torres
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.
authors: Vicente
authors: V
authors: Valenzuela
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.
authors: Danilo B
authors: DB
authors: Medinas
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors: Pablo
authors: P
authors: Rozas
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Neurounion Biomedical Foundation, CENPAR, Santiago, Chile.
authors: Rene L
authors: RL
authors: Vidal
authors: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Rodrigo
authors: R
authors: Lopez-Gonzalez
authors: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Johnny
authors: J
authors: Salameh
authors: Department of Anatomy, Medical School, Universidad Católica de Chile, Santiago, Chile.
authors: Sara
authors: S
authors: Fernandez-Collemann
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Neurounion Biomedical Foundation, CENPAR, Santiago, Chile.
authors: Natalia
authors: N
authors: Muñoz
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Neurounion Biomedical Foundation, CENPAR, Santiago, Chile.
authors: Soledad
authors: S
authors: Matus
authors: Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors: Ricardo
authors: R
authors: Armisen
authors: Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors: Alfredo
authors: A
authors: Sagredo
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors: Karina
authors: K
authors: Palma
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors: Thergiory
authors: T
authors: Irrazabal
authors: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Sandra
authors: S
authors: Almeida
authors: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Paloma
authors: P
authors: Gonzalez-Perez
authors: Department of Neurology and Neurosurgery, Faculty of Medicine, University of Chile, Santiago, Chile Faculty of Medicine, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile.
authors: Mario
authors: M
authors: Campero
authors: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Fen-Biao
authors: FB
authors: Gao
authors: Department of Anatomy, Medical School, Universidad Católica de Chile, Santiago, Chile.
authors: Pablo
authors: P
authors: Henny
authors: Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile.
authors: Brigitte
authors: B
authors: van Zundert
authors: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors: Lloyd W
authors: LW
authors: Ruddock
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Anatomy and Developmental Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.
authors: Miguel L
authors: ML
authors: Concha
authors: 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.
authors: Juan P
authors: JP
authors: Henriquez
authors: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA robert.brown@umassmed.edu clahetz@med.uchile.cl chetz@hsph.harvard.edu.
authors: Robert H
authors: RH
authors: Brown
authors: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA robert.brown@umassmed.edu clahetz@med.uchile.cl chetz@hsph.harvard.edu.
authors: Claudio
authors: C
authors: Hetz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D004576:Electromyography; D004625:Embryo, Nonmammalian; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D006801:Humans; D018345:Mice, Knockout; D009046:Motor Neurons / Q000473:pathology*; D009154:Mutation; D016501:Neurites / Q000473:pathology; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D011393:Procollagen-Proline Dioxygenase; C526497:P4HB protein, human; C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human
keywords: ERp57; PDIA1; amyotrophic lateral sclerosis; protein disulfide isomerase