Disulfide Bonding in Neurodegenerative Misfolding Diseases

In recent years an increasing number of neurodegenerative diseases has been linked to the misfolding of a specific protein and its subsequent accumulation into aggregated species, often toxic to the cell. Of all the factors that affect the behavior of these proteins, disulfide bonds are likely to be important, being very conserved in protein sequences and being the enzymes devoted to their formation among the most conserved machineries in mammals. Their crucial role in the folding and in the function of a big fraction of the human proteome is well established. The role of disulfide bonding in preventing and managing protein misfolding and aggregation is currently under investigation. New insights into their involvement in neurodegenerative diseases, their effect on the process of protein misfolding and aggregation, and into the role of the cellular machineries devoted to disulfide bond formation in neurodegenerative diseases are emerging. These studies mark a step forward in the comprehension of the biological base of neurodegenerative disorders and highlight the numerous questions that still remain open. 1. Introduction Neurodegenerative misfolding diseases (NMD) are a group of diseases involving the misfolding of one or two proteins and their accumulation into aggregated species toxic to neurons, leading to a wide range of neurological symptoms (Table 1). Among these are Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), prion-related disorders (PrDs), and amyotrophic lateral sclerosis (ALS). In each case a specific protein loses its functional structure to populate partially unfolded species that reorganize themselves into polymeric structures with different degrees of ordered structure, from oligomers to amyloid fibrils [1]. Table 1: Presence of disulfide bonds in proteins involved in neurodegenerative misfolding diseases. The fate of a protein depends on two major factors, its sequence and its cellular environment. From the sequence perspective, many studies have identified several features of the amino acid sequence of a protein that help predict its aggregation behavior, such as charge, hydrophobicity, patterns of polar and nonpolar residues, and tendency to form secondary structures [2, 3]. After peptide bond, the disulfide bond is the most common covalent link between amino acids in proteins. Disulfide bonds are known to stabilize proteins thermodynamically by decreasing the entropy of the unfolded state, to increase mechanical stability and to confine conformational changes [4]. From the cellular environment point