The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models
Summary: Pathological forms of TAR DNA-binding protein 43 (TDP-43) are present in almost all cases of amyotrophic lateral sclerosis (ALS), and 20% of familial ALS cases are due to mutations in superoxide dismutase 1 (SOD1). Redox regulation is critical to maintain cellular homeostasis, although how...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220302820 |
| _version_ | 1818130660601102336 |
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| author | Sonam Parakh Sina Shadfar Emma R. Perri Audrey M.G. Ragagnin Claudia V. Piattoni Mariela B. Fogolín Kristy C. Yuan Hamideh Shahheydari Emily K. Don Collen J. Thomas Yuning Hong Marcelo A. Comini Angela S. Laird Damian M. Spencer Julie D. Atkin |
| author_facet | Sonam Parakh Sina Shadfar Emma R. Perri Audrey M.G. Ragagnin Claudia V. Piattoni Mariela B. Fogolín Kristy C. Yuan Hamideh Shahheydari Emily K. Don Collen J. Thomas Yuning Hong Marcelo A. Comini Angela S. Laird Damian M. Spencer Julie D. Atkin |
| author_sort | Sonam Parakh |
| collection | DOAJ |
| description | Summary: Pathological forms of TAR DNA-binding protein 43 (TDP-43) are present in almost all cases of amyotrophic lateral sclerosis (ALS), and 20% of familial ALS cases are due to mutations in superoxide dismutase 1 (SOD1). Redox regulation is critical to maintain cellular homeostasis, although how this relates to ALS is unclear. Here, we demonstrate that the redox function of protein disulfide isomerase (PDI) is protective against protein misfolding, cytoplasmic mislocalization of TDP-43, ER stress, ER-Golgi transport dysfunction, and apoptosis in neuronal cells expressing mutant TDP-43 or SOD1, and motor impairment in zebrafish expressing mutant SOD1. Moreover, previously described PDI mutants present in patients with ALS (D292N, R300H) lack redox activity and were not protective against ALS phenotypes. Hence, these findings implicate the redox activity of PDI centrally in ALS, linking it to multiple cellular processes. They also imply that therapeutics based on PDI's redox activity will be beneficial in ALS. |
| first_indexed | 2024-12-11T08:08:34Z |
| format | Article |
| id | doaj.art-5d7c8645d1a843979d2e77a8fb26be55 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-11T08:08:34Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-5d7c8645d1a843979d2e77a8fb26be552022-12-22T01:14:57ZengElsevieriScience2589-00422020-05-01235The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish ModelsSonam Parakh0Sina Shadfar1Emma R. Perri2Audrey M.G. Ragagnin3Claudia V. Piattoni4Mariela B. Fogolín5Kristy C. Yuan6Hamideh Shahheydari7Emily K. Don8Collen J. Thomas9Yuning Hong10Marcelo A. Comini11Angela S. Laird12Damian M. Spencer13Julie D. Atkin14Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; Corresponding authorCentre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, AustraliaCentre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, AustraliaCentre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, AustraliaCell Biology Unit, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, UruguayCell Biology Unit, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, UruguayCentre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, AustraliaCentre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, AustraliaCentre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, AustraliaDepartment of Physiology, Anatomy and Microbiology, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, AustraliaDepartment of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, AustraliaCell Biology Unit, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, Uruguay; Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, UruguayCentre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, AustraliaDepartment of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, AustraliaCentre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, AustraliaSummary: Pathological forms of TAR DNA-binding protein 43 (TDP-43) are present in almost all cases of amyotrophic lateral sclerosis (ALS), and 20% of familial ALS cases are due to mutations in superoxide dismutase 1 (SOD1). Redox regulation is critical to maintain cellular homeostasis, although how this relates to ALS is unclear. Here, we demonstrate that the redox function of protein disulfide isomerase (PDI) is protective against protein misfolding, cytoplasmic mislocalization of TDP-43, ER stress, ER-Golgi transport dysfunction, and apoptosis in neuronal cells expressing mutant TDP-43 or SOD1, and motor impairment in zebrafish expressing mutant SOD1. Moreover, previously described PDI mutants present in patients with ALS (D292N, R300H) lack redox activity and were not protective against ALS phenotypes. Hence, these findings implicate the redox activity of PDI centrally in ALS, linking it to multiple cellular processes. They also imply that therapeutics based on PDI's redox activity will be beneficial in ALS.http://www.sciencedirect.com/science/article/pii/S2589004220302820NeurogeneticsMolecular BiologyNeuroscience |
| spellingShingle | Sonam Parakh Sina Shadfar Emma R. Perri Audrey M.G. Ragagnin Claudia V. Piattoni Mariela B. Fogolín Kristy C. Yuan Hamideh Shahheydari Emily K. Don Collen J. Thomas Yuning Hong Marcelo A. Comini Angela S. Laird Damian M. Spencer Julie D. Atkin The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models iScience Neurogenetics Molecular Biology Neuroscience |
| title | The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models |
| title_full | The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models |
| title_fullStr | The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models |
| title_full_unstemmed | The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models |
| title_short | The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models |
| title_sort | redox activity of protein disulfide isomerase inhibits als phenotypes in cellular and zebrafish models |
| topic | Neurogenetics Molecular Biology Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220302820 |
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