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

doi:10.1016/j.isci.2020.101097

The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models

iScience. 2020 May 22;23(5):101097. doi: 10.1016/j.isci.2020.101097. Epub 2020 Apr 25.

Authors

Affiliations

¹ 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. Electronic address: sonam.parakh@mq.edu.au.
² Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
³ 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.
⁴ Cell Biology Unit, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, Uruguay.
⁵ Department of Physiology, Anatomy and Microbiology, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
⁶ Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
⁷ 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.
⁸ Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.

Abstract

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.

Keywords: Molecular Biology; Neurogenetics; Neuroscience.