Proteostasis and pathogenesis: Unraveling the complexity of protein misfolding disorders

Within the cellular milieu, protein molecules must fold into precise three-dimensional structures to attain functionality. Protein chains can assume many misfolded states during this critical process. Such errant configurations are unstable and can aggregate into toxic misfolded conformations. In protein misfolding disorders, polypeptides are folded in an aberrant manner, resulting in non-functional and often pathogenic states. Protein folding is fundamental to biological function, and disruption of the process can result in toxic aggregates, such as oligomers and amyloid fibrils, which are implicated in a variety of diseases, particularly neurodegenerative diseases such as Alzheimer's and Parkinson's. Here, we examine the delicate interplay of forces that determine the native conformation of proteins and how perturbations in this balance lead to disease. A critical aspect of our discussion is the cell's proteostasis network, a complex network of molecular chaperones and regulators responsible for regulating protein folding and maintaining the health of the cell. In this chapter, we discuss how intrinsic protein properties, post-translational modifications, and extrinsic environmental factors can destabilize proteins, thereby resulting in their misfolding. Several pathogenic mechanisms will be elucidated, including the progression from a misfolded protein to the development of disease phenotypes. Next, the chapter will present an overview of the current therapeutic approaches to mitigate the diseases caused by protein misfolding. Using the latest findings in clinical and experimental research, we will evaluate the therapeutic landscape, ranging from small-molecule inhibitors to chaperone-based therapies.