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

• DOI: 10.1016/j.isci.2020.101097
• Publication Date: 2020-04-25T06:41:25Z
• Authors: 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
• Keywords: 0301 basic medicine; 03 medical and health sciences; Science; Q; Neurogenetics; Molecular Biology; Article; Neuroscience

Pathological forms of TAR DNA-binding protein 43 (TDP-43) are present in almost all cases amyotrophic lateral sclerosis (ALS), and 20% familial ALS due to mutations superoxide dismutase 1 (SOD1). Redox regulation is critical maintain cellular homeostasis, although how this relates unclear. Here, we demonstrate that the redox function disulfide isomerase (PDI) protective against misfolding, cytoplasmic mislocalization TDP-43, ER stress, ER-Golgi transport dysfunction, apoptosis neuronal cells expressing mutant TDP-43 or SOD1, motor impairment zebrafish SOD1. Moreover, previously described PDI mutants patients with (D292N, R300H) lack activity were not phenotypes. Hence, these findings implicate centrally ALS, linking it multiple processes. They also imply therapeutics based on PDI's will be beneficial ALS.