Abstract
Free radicals are unstable chemical reactive species produced during Redox dyshomeostasis (RDH) inside living cells and are implicated in the pathogenesis of various neurodegenerative diseases. One of the most complicated and life-threatening motor neurodegenerative diseases (MND) is amyotrophic lateral sclerosis (ALS) because of the poor understanding of its pathophysiology and absence of an effective treatment for its cure. During the last 25 years, researchers around the globe have focused their interest on copper/zinc superoxide dismutase (Cu/Zn SOD, SOD1) protein after the landmark discovery of mutant SOD1 (mSOD1) gene as a risk factor for ALS. Substantial evidence suggests that toxic gain of function due to redox disturbance caused by reactive oxygen species (ROS) changes the biophysical properties of native SOD1 protein thus, instigating its fibrillization and misfolding. These abnormal misfolding aggregates or inclusions of SOD1 play a role in the pathogenesis of both forms of ALS, i.e., Sporadic ALS (sALS) and familial ALS (fALS). However, what leads to a decrease in the stability and misfolding of SOD1 is still in question and our scientific knowledge is scarce. A large number of studies have been conducted in this area to explore the biochemical mechanistic pathway of SOD1 aggregation. Several studies, over the past two decades, have shown that the SOD1-catalyzed biochemical reaction product hydrogen peroxide (H2O2) at a pathological concentration act as a substrate to trigger the misfolding trajectories and toxicity of SOD1 in the pathogenesis of ALS. These toxic aggregates of SOD1 also cause aberrant localization of TAR-DNA binding protein 43 (TDP-43), which is characteristic of neuronal cytoplasmic inclusions (NCI) found in ALS. Here in this review, we present the evidence implicating the pivotal role of H2O2 in modulating the toxicity of SOD1 in the pathophysiology of the incurable and highly complex disease ALS. Also, highlighting the role of H2O2 in ALS, we believe will encourage scientists to target pathological concentrations of H2O2 thereby halting the misfolding of SOD1.
Highlights
Free radicals, in the context of living cells, are bio-reactive species
Cheng Xu and colleagues (2018) [21], explained how the pathological concentration of H2 O2 regulates the redox biology of Cys111 and regulates the misfolding and toxicity of superoxide dismutase 1 (SOD1) and TAR-DNA binding protein 43 (TDP-43) associated with amyotrophic lateral sclerosis (ALS) and suggested that sulfenic acid modification of wSOD1 play a crucial role in the pathogenesis of sporadic ALS
Sulphenylation provokes the gain of function and thereby, act as a critical pathological marker in the pathogenicity of oligomerization and aggregation of SOD1 to neurotoxic misfolded oligomers and aggreALS
Summary
In the context of living cells, are bio-reactive species. They are unstable, short-lived, and highly reactive chemical species. The discovery of mutations in the superoxide dismutase 1 (SOD1) gene that encodes antioxidant SOD1 enzyme, made it possible to understand the progression of the disease. Substantial evidence has shown that abnormal conformational change in the structure of SOD1 protein causes misfolding and aggregation, and is thought to have neurotoxic properties, which are observed in both forms of ALS [8,9,10]. A large body of evidence has shown that redox dysregulation of SOD1 during oxidative stress is largely involved in changing the biochemical and biophysical properties of SOD1 causing its abnormal aggregation and misfolding [11,12,13,14,15,16], which is evident in the cellular toxicity observed in ALS [17,18,19,20]. We explore the role of H2 O2 as a major determinant in the pathophysiology of ALS
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