ArticleThe EMBO journal2016
ALS-linked protein disulfide isomerase variants cause motor dysfunction.
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Article in The EMBO journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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61citing papers in PubMed
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61 citing papers in PubMed, 115 citations in OpenAlex.
- Protein disulphide isomerase protects against ALS/FTD phenotypes associated with cyclin F in zebrafish and cellular models.Redox report : communications in free radical research · 2026Article
- Enzyme-Inspired Design of Redox-Active Molecules for Promotion of Oxidative Protein Folding.Chembiochem : a European journal of chemical biology · 2026Review
- Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.Journal of neurochemistry · 2026Review
- Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis.Molecular neurobiology · 2025Review
- Artificial enforcement of the unfolded protein response reduces disease features in multiple preclinical models of ALS/FTD.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Mechanistic basis of activation and inhibition of protein disulfide isomerase by allosteric antithrombotic compounds.Journal of thrombosis and haemostasis : JTH · 2025Article
- Overexpression of autophagy enhancer PACER/RUBCNL in neurons accelerates disease in the SOD1Biological research · 2024Article
- Therapeutic Options of Crystallin Mu and Protein Disulfide Isomerase A3 for Cuprizone-Induced Demyelination in Mouse Hippocampus.Neurochemical research · 2024Article
- Vitamin D Deficiency Does Not Affect Cognition and Neurogenesis in Adult C57Bl/6 Mice.Nutrients · 2024Article
- Protein Disulfide Isomerase Endoplasmic Reticulum Protein 57 (ERp57) is Protective Against ALS-Associated Mutant TDP-43 in Neuronal Cells.Neuromolecular medicine · 2024Article
- Biological mechanisms and clinical significance of endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) in human cancer.Journal of experimental & clinical cancer research : CR · 2024Review
- Molecular hallmarks of ageing in amyotrophic lateral sclerosis.Cellular and molecular life sciences : CMLS · 2024Review
- Enzymatic and synthetic regulation of polypeptide folding.Chemical science · 2024Review
- Exploring the Influence of Zinc Ions on the Conformational Stability and Activity of Protein Disulfide Isomerase.International journal of molecular sciences · 2024Article
- Protein Assembly Modulation: A New Approach to Amyotrophic Lateral Sclerosis (ALS) Therapeutics.Journal of experimental neurology · 2024Article
- Biochemical analysis of Komagataella phaffii oxidative folding proposes novel regulatory mechanisms of disulfide bond formation in yeast.Scientific reports · 2023Article
- Passing the post: roles of posttranslational modifications in the form and function of extracellular matrix.American journal of physiology. Cell physiology · 2023Review
- A KO mouse model for the lncRNA Lhx1os produces motor neuron alterations and locomotor impairment.iScience · 2023Article
- Impaired communication at the neuromotor axis during Degenerative Cervical Myelopathy.Frontiers in cellular neuroscience · 2023Article
- Mutation in protein disulfide isomerase A3 causes neurodevelopmental defects by disturbing endoplasmic reticulum proteostasis.The EMBO journal · 2022Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
32 authors at 12 institutions in 3 countries.
Ute WoehlbierBiomedical 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.
Alicia ColomboProgram 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.
Mirva J SaaranenBiocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
Viviana PérezDepartment of Cell Biology, Faculty of Biological Sciences, Millennium Nucleus of Regenerative Biology, Center for Advanced Microscopy (CMA Bio-Bio), Universidad de Concepción, Concepción, Chile.
Jorge OjedaDepartment of Cell Biology, Faculty of Biological Sciences, Millennium Nucleus of Regenerative Biology, Center for Advanced Microscopy (CMA Bio-Bio), Universidad de Concepción, Concepción, Chile.
Fernando J BustosFaculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile.
Catherine I AndreuBiomedical 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.
Mauricio TorresBiomedical 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.
Vicente ValenzuelaBiomedical 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.
Danilo B MedinasBiomedical 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.
Pablo RozasBiomedical 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.
Rene L VidalBiomedical 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.
Rodrigo Lopez-GonzalezDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Johnny SalamehDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Sara Fernandez-CollemannDepartment of Anatomy, Medical School, Universidad Católica de Chile, Santiago, Chile.
Natalia MuñozBiomedical 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.
Soledad MatusBiomedical 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.
Ricardo ArmisenProgram of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
Alfredo SagredoProgram of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
Karina PalmaBiomedical 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.
Thergiory IrrazabalBiomedical 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.
Sandra AlmeidaDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Paloma Gonzalez-PerezDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Mario CamperoDepartment of Neurology and Neurosurgery, Faculty of Medicine, University of Chile, Santiago, Chile Faculty of Medicine, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile.
Fen-Biao GaoDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Pablo HennyDepartment of Anatomy, Medical School, Universidad Católica de Chile, Santiago, Chile.
Brigitte van ZundertFaculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile.
Lloyd W RuddockBiocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
Miguel L ConchaBiomedical 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.
Juan P HenriquezDepartment of Cell Biology, Faculty of Biological Sciences, Millennium Nucleus of Regenerative Biology, Center for Advanced Microscopy (CMA Bio-Bio), Universidad de Concepción, Concepción, Chile.
Robert H BrownDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA robert.brown@umassmed.edu clahetz@med.uchile.cl chetz@hsph.harvard.edu.
Claudio HetzBiomedical 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.
University of Chile · CLUniversity of Massachusetts Chan Medical School · USCenter for Climate and Resilience Research · CLNeurounion Biomedical Foundation · CLUniversity of Concepción · CLPontificia Universidad Católica de Chile · CLUniversidad Andrés Bello · CLUniversity of Oulu · FIHarvard University · USHospital Clínico de la Universidad de Chile · CLUniversidad del Desarrollo · CLUniversidad Mayor · CL
Funding
Investigating Common Molecular Pathogenic Pathways in Frontotemporal Dementia Patients iPSC-Derived NeuronsR01NS057553 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Fen-Biao Gao · 2008 to 2026
$4.5MInvestigating Pathogenic Mechanisms of Frontotemporal Dementia Caused by Mutations in CHMP2B and TBK1R37NS057553 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI GAO, FEN-BIAO · 2018 to 2024
$4.3MHigh-Throughput Genomic Approaches to Identify ALS GenesR01NS050557 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI BROWN, ROBERT H. · 2005 to 2009
$2.5MHoward Hughes Medical InstituteNINDS NIH HHS 1R01NS050557NINDS NIH HHS NS057553-07NINDS NIH HHS R01 NS050557NINDS NIH HHS R01 NS057553NINDS NIH HHS R37 NS057553
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.
Indexed as
Amyotrophic Lateral SclerosisAnimalsAnimals, Genetically ModifiedElectromyographyEmbryo, NonmammalianEndoplasmic Reticulum StressHumansMice, KnockoutMotor NeuronsMutationNeuritesProcollagen-Proline DioxygenaseProtein Disulfide-IsomerasesZebrafishP4HB protein, humanPDIA3 protein, humanPdia3 protein, mouseProcollagen-Proline DioxygenaseProtein Disulfide-Isomerasesamyotrophic lateral sclerosisERp57PDIA1protein disulfide isomerase
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