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

Sonam Parakh,Yuning Hong,Collen J Thomas,Angela S Laird,Mariela B Fogolín,Damian M Spencer,Sina Shadfar,Marcelo A Comini,Audrey M.G Ragagnin,Julie D Atkin,Emma R Perri,Claudia V Piattoni,Kristy C Yuan,Hamideh Shahheydari,Emily K Don

doi:10.1016/j.isci.2020.101097

Sonam Parakh, Yuning Hong + Show 13 more

Open Access

https://doi.org/10.1016/j.isci.2020.101097

Copy DOI

Abstract

SummaryPathological 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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons in the brain and spinal cord, leading to progressive loss of motor control (Angelini, 2018), which is related genetically and clinically to frontotemporal dementia (FTD)
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)
We demonstrate that the redox function of protein disulfide isomerase (PDI) is protective against protein misfolding, cytoplasmic mislocalization of TDP-43, endoplasmic reticulum (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

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons in the brain and spinal cord, leading to progressive loss of motor control (Angelini, 2018), which is related genetically and clinically to frontotemporal dementia (FTD). Redox dysregulation is caused by an imbalance between the levels of reactive radicals and antioxidants, and oxidative stress refers to the disruption of redox signaling and control. This changes the cellular redox state, modifies redox proteins, and disrupts redox-regulated mechanisms (Ursini et al, 2016). Redox homeostasis is associated with many pathological mechanisms implicated in ALS, including protein misfolding, endoplasmic reticulum (ER) dysfunction, defects in cellular trafficking, and apoptosis (Atkin et al, 2014; Calabrese et al, 2010; Chang et al, 2013; Cohen et al, 2012; Soo et al, 2015; Walker et al, 2013)

Results

Discussion

Conclusion