Cellular Cysteine Network and Neurodegeneration

Oxidative stress is strongly linked to neurodegeneration and oxidative species can modify many amino acids and proteins in the brain. Cysteine amino acid is most susceptible to oxidative post-translational modifications (PTMs). Reversible or irreversible cysteine PTMs can cause dyshomeostasis, which further continued to cellular damage. Many cysteine dependent proteins and many non-proteins using cysteine as their structural components are affected by oxidative stress. Several cysteine dependent enzymes are acting as antioxidants. Cysteine is a major contributor to glutathione (GSH) and superoxide dismutase (SOD) synthesis. Cysteine precursor N-acetylcysteine (NAC) supplementation is proven as a potent free radical scavenger and increase brain antioxidants and subsequently potentiates the natural antioxidant cellular defense mechanism. Thus, in this chapter, the authors explore the linkage of cellular cysteine networks and neurodegenerative disorders.

PINK1/Parkin in Neurodegenerative Disorders

PTEN-induced kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene, is thought to protect cells from stress-induced mitochondrial dysfunction. The activity of PINK1 facilitates the binding of Parkin protein with depolarized mitochondria to induce autophagy. Mutations of PINK1causes a type of autosomal recessive early-onset Parkinson's disease. Cell depends on the surveillance systems or mechanisms like protein quality control to handle the alterations in the proteins that are induced because of these mutations. These mutant proteins are found to be pathogenic and are reported to be related to various neurodegenerative disorders. This chapter focuses on the role of PINK1/Parkin in mitochondria quality control and its subsequent effect in neurodegeneration.

Molecular Interactions of α-Synuclein, Mitochondria, and Cellular Degradation Pathways in Parkinson's Disease

Parkinson's disease (PD) has been reported to be the most common neurodegenerative diseases all over the world. Several proteins are associated and responsible for causing PD. One such protein is α-synuclein. This chapter discusses the role of α-synuclein in PD. Various genetic and epigenetic factors, which cause structural and functional changes for α-synuclein, have been described. Several molecular mechanisms, which are involved in regulating mitochondrial and lysosomal related pathways and are linked to α-synuclein, have been discussed in detail. The knowledge gathered is further discussed in terms of using α-synuclein as a diagnostic marker for PD and as a novel therapeutic target for the same.

Protein Quality Control in Neurodegeneration and Neuroprotection

Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.

Cysteine in Alzheimer's Disease

Alzheimer's disease (AD) is characterized by selective loss of neurons in the hippocampus and neocortex due to abnormalities in proteins, mainly Aβ peptide and tau protein, in the form of abnormal protein aggregations or depositions in neurons. Recently oxidative/nitrosative stress has been identified as an important facilitator of neurodegeneration in AD. Cysteine-dependent proteins are known to be associated with the neurodegenerative process. Such cysteine-dependent enzyme proteins are proteases, antioxidant enzymes, kinases, phosphatases, and also non-enzymatic proteins such that utilize cysteine as a structural part of the catalytic site. This chapter deals with the role of cysteine in handling reactive oxygen/nitrogen species during oxidative/nitrosative stress and posttranslational modification of proteins causing protein misfolding or protein aggregation during neurodegeneration associated with AD.

Molecular Chaperones in Neurodegeneration

Cellular chaperones are essential players to this protein quality control network that functions to prevent protein misfolding, refold misfolded proteins, or degrade them, thereby maintaining neuronal proteostasis. Moreover, overexpression of cellular chaperones is considered to inhibit protein aggregation and apoptosis in various experimental models of neurodegeneration. Alterations or downregulation of chaperone machinery by age-related decline, molecular crowding, or genetic mutations are regarded as key pathological hallmarks of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Prion diseases. Therefore, chaperones may serve as potential therapeutic targets in these diseases. This chapter presents a generalized view of misfolding and aggregation of proteins in neurodegeneration and then critically analyses some of the known cellular chaperones and their role in several neurodegenerative disorders.

Multifarious Role of BAG3 in Neurodegenerative Disorders

The glial cells along with cells of hematopoietic origin and microvascular endothelia work together to maintain the normal development and/or functioning of the nervous system. Disruption in functional coordination among these cells interrupts the efficiency of the nervous system, leading to neurodegeneration. Various proteins in the nerve cells maintain the normal signaling mechanism with these cells and throughout the body. Structural/functional disorganization of these proteins causes neurodegenerative disorders. The molecular mechanisms involved in these phenomena are yet to be explored extensively from therapeutic perspectives. Through this chapter, the authors have elaborated on less known protein Bcl-2 associated athanogene 3 (BAG3) involved in neurodegeneration. They have explored BAG3 protein and its role in neurodegeneration, protein homeostasis, its mechanism of action, its uses as a drug target, and its uses as a possible diagnostic marker of neurodegeneration.

Beclin 1 Complex and Neurodegenerative Disorders

Beclin1 is the mammalian orthologue of yeast Atg6/vacuolar protein sorting-30 (VPS30). Beclin1 interacts with various biological macromolecules like ATG14, BIF-1, NRBF2, RUBICON, UVRAG, AMBRA1, HMGB1, PINK1, and PARKIN. Such interactions promote Beclin1-PI3KC3 complex formation. Autophagy is blocked in apoptosis owing to the breakdown of Beclin1 by caspase whereas autophagy induction inhibits effector caspase degradation, therefore, blocks apoptosis. Thus, the Beclin1 is an essential biomolecular species for cross-regulation between autophagy and apoptosis. Various studies carried out in neurodegenerative animal models associated with aggregated proteins have confirmed that multifunctional Beclin1 protein is necessary for neuronal integrity. The role of Beclin1 protein has been investigated and was reported in various human neurodegeneration disorders. This chapter aims to provide an insight into the role of Beclin1 in the development of neurodegenerative disorders.

ER Stress Signaling in Alzheimer's Disease

Alzheimer's disease (AD) is the most common etiology of dementia amongst aged individuals and a principal public health-related abnormality. It is considered as a multifactorial disorder, with no particular origin identified, and also some modifiable, as well as non-modifiable threats are correlated with its progression and development. The endoplasmic reticulum (ER) stress response is considered as a key process in the pathogenesis of AD. In this chapter, the authors present a summary of related transmembrane kinase proteins responsible for the onset of AD as well as show the interrelationship between ER stress and AD. Finally, the authors demonstrate the therapeutics intervention for AD diagnosis by highlighting the current practices to advance novel therapies.

Proteostasis and Neurodegeneration

Proteostasis or protein homeostasis consists of a complex interrelated cellular system that controls several steps of protein quality and function from the initial step of synthesis as well as folding, and eventually degradation over enormous biochemical pathways. Proteostasis involves controlling protein folding, modification of the post-translational protein, and degradation of misfolded protein. However, the failure of proteostasis has resulted to produce a toxic protein that leads to disrupt aging and neurodegeneration. Additionally, endoplasmic reticulum degradation and autophagy dysfunction may outcome in cellular additional stress that is responsible for cell death. Consequently, proteostasis targets provide an element of a promising neuronal protective therapeutic method to improve the development of these diseases as well. In this chapter, the authors represent the current knowledge regarding how cellular proteostasis interruption contributes to progress neurodegenerative disorders.