Cellular Cysteine Network and Neurodegeneration

Introduction

Cellular metabolic reactions are consequently producing free radicals. Amongst all, chemically reactive species of nitrogen (RNS), oxygen (ROS) as well as sulfur (RSS) are produced as a part of cellular signal transductions (Jones, 2006). These reactive radicals have a modifying effect on susceptible amino acids, proteins and other cellular components to get structural and functional changes. Specifically, cysteine residues are more sensitive to redox alterations. Each cell always has a limited amount of ROS or RNS but, when their basal level goes beyond the limit, antioxidant systems are stimulated as a defense mechanism. The body is provided with various pathways to compensate for increased free radicals and redox-active molecules (Sbodio et al., 2017).

Increased levels of ROS have adverse or damaging effects on cell leading to pathological conditions. To counteract the ROS mediated oxidative damage, the cell has provided with the chain of active antioxidant substances regulating redox homeostasis, i.e. superoxide dismutase (SOD), catalase, peroxidases, and heme oxygenase like enzymatic as well as glutathione and vitamin C like non-enzymatic antioxidants (Calabrese et al. 2010). Disturbed balance of damaging oxidative stress and protective antioxidants can result in increased oxidative stress which is not counterbalanced by the cellular antioxidant system. If this disturbed balance of oxidant-antioxidant shifted in favor of the former, the condition is called oxidative stress which also concerned with changing redox signaling and control. Redox dysregulation can affect proteins, lipids, nucleic acids and carbohydrates and many more components of the cell, which is a major contributing factor in the pathophysiology of neurodegenerative disorders viz. amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD). Increased oxidative stress along with associated cellular damage, deals with disease progression (Sbodio et al., 2017).

Normally, protein delivery to the endoplasmic reticulum (ER) is balanced by cell using unfolded protein. During proteins misfolding reaction, either abnormal protein aggregates are broken or protein refolds; or recycled by proteasome if proteins cannot be reversed by refolding. Abnormal protein aggregation, modifying conformations of proteins, is associated with many disorders or diseases. AD, PD, HD, ALS and Friedreich’s ataxia (FRDA) are considered as protein conformational diseases (Tabner et al., 2001; Calabrese et al., 2010). In the cell, these abnormal protein aggregates may arise from ER dysfunction, mitochondrial dysfunction, abnormally increased in reactive oxygen species (ROS), leading to oxidative stress and cellular antioxidants and anti-apoptotic substances activates pro-survival pathway to combat this increased oxidative stress (Calabrese et al., 2010).

The production of ROS is directly proportional to metabolic rate and inversely proportional to lifespan. Many cell organelles, biochemical and physiological processes produce ROS (Adelman et al., 1988). Amongst all, the major contributors are mitochondria. Mitochondrial components like nuclear DNA, mitochondrial DNA, and associated proteins are also damaged by oxidative stress which can further damage the cell (Calabrese et al., 2000). This chapter focuses on the effect of oxidative stress on the antioxidant system of the brain specifically cysteine modifications due to redox dysregulation and its role in various neurodegenerative disorders.