The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models
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
Affiliations
Sonam Parakh
Centre 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 author
Sina Shadfar
Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
Emma R. Perri
Centre 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
Audrey M.G. Ragagnin
Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
Claudia V. Piattoni
Cell Biology Unit, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, Uruguay
Mariela B. Fogolín
Cell Biology Unit, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, Uruguay
Kristy C. Yuan
Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
Hamideh Shahheydari
Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
Emily K. Don
Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
Collen J. Thomas
Department of Physiology, Anatomy and Microbiology, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
Yuning Hong
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
Marcelo A. Comini
Cell 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, Uruguay
Angela S. Laird
Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
Damian M. Spencer
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
Julie D. Atkin
Centre 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
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.
