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.
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Protein production, quality control, as well as degradation of entire proteins are required firmly to regulate and maintain cellular function and health (Newton et al., 2019). To employ its biological activity and function they must require to appropriate fold with the conformation of three-dimensional structure (Kurtishi et al., 2019). Neuronal cell death and neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), as well as prion disease (pD) are sometimes occurred by protein misfolding (Coppede and Migliore, 2015; Shiwaku and Okazawa, 2015).
The common risk factors of neurodegenerative diseases are caused by environmental factors, oxidative stress, protein dysfunction, and aging which ultimately produce distinctive pathologies (Coppede and Migliore, 2015). Among them, protein aggregation and misfolding is a general feather in neurodegenerative disorders. By balancing protein misfolding as well as foldings are major in protecting the proteome functionality (Hipp et al., 2014). However, the accumulation of inactive misfolded proteins may result in stress responses in cells as well as organelles (Rao and Bredesen, 2004). Unfolded protein response (UPR) and proteostasis is maintained by endoplasmic reticulum (ER) that is triggered via ER stress and protein accumulation. UPR stimulates protein folding as well as decreases protein levels of ER through translation mitigation, proteasomal degradation, and autophagy (Plate and Wiseman, 2017). Autophagy furthermore plays an important function in proteostasis as a result of its capability to destroy aggregate proteins that cannot be degraded through the proteasome system (Dong and Cui, 2019). For instance, in the autophagy system autophagosome binds to lysosome as a consequence of degrading as well as recycle whole organelles which encourage cell survival factors to control neurodegeneration (Rahman and Rhim, 2017). Proteins are degraded by autophagy and the proteasome use ubiquitination to recruit target proteins as well (Rahman and Rhim, 2017; Zientara-Rytter and Subramani, 2019). Ubiquitination and additional covalent attachments, for example, SUMOylation, phosphorylation, and oxidation control regular proteome function (Colignon et al., 2019).
Additionally, post-translational modifications (PTMs) of proteins also shown to stimulates protein aggregation in numerous neurodegenerative syndromes (Owen and Shewmaker, 2019). Disease-associated proteins accumulation cause in the aggregation of protein which leads to proteotoxicity that causes a problem in post-mitotic neurons emphasizing the strong connection between neurodegeneration and aging (McAlary et al., 2019). Moreover, mitochondrial proteostasis is similarly crucial for the survival of the cell, however, its dysfunction may also lead to the increase of reactive oxygen species (ROS) that could be disrupted to general cellular proteostasis (Veeresh et al., 2019). Certainly, a dysfunction of mitochondrial proteostasis can lead to permanent apoptosis induction (Moehle et al., 2019). In this chapter, the author summarizes essential factors that disturb proteostasis as well as additionally describe how dysfunction of proteostasis eventually affects neurodegenerative disorders.