Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress

Abstract

Protein homeostasis or proteostasis is an essential balance of cellular protein levels mediated through an extensive network of biochemical pathways that regulate different steps of the protein quality control, from the synthesis to the degradation. All proteins in a cell continuously turn over, contributing to development, differentiation, and aging. Due to the multiple interactions and connections of proteostasis pathways, exposure to stress conditions may cause various types of protein damage, altering cellular homeostasis and disrupting the entire network with additional cellular stress. Furthermore, protein misfolding and/or alterations during protein synthesis results in inactive or toxic proteins, which may overload the degradation mechanisms. The maintenance of a balanced proteome, preventing the formation of impaired proteins, is accomplished by two major catabolic routes: the ubiquitin proteasomal system (UPS) and the autophagy-lysosomal system. The proteostasis network is particularly important in nondividing, long-lived cells, such as neurons, as its failure is implicated with the development of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. These neurological disorders share common risk factors such as aging, oxidative stress, environmental stress, and protein dysfunction, all of which alter cellular proteostasis, suggesting that general mechanisms controlling proteostasis may underlay the etiology of these diseases. In this review, we describe the major pathways of cellular proteostasis and discuss how their disruption contributes to the onset and progression of neurodegenerative diseases, focusing on the role of oxidative stress.

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“…Oxidative stress is one of the major drivers of protein misfolding that, accumulating and aggregating as insoluble inclusions can determine neurodegeneration ( Hohn et al, 2020 , Knowles et al, 2014 ). It is known that Nfr2 promotes the clearance of oxidized or otherwise damaged proteins through the autophagy mechanism ( Tang et al, 2019 ).…”

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“…Proteostasis is essential for cell health and viability and is ensured by the coordinated regulation of protein translation, folding, trafficking, and degradation. When the equilibrium among these mechanisms is lost, aberrant proteostasis occurs and this represents a central molecular hallmark of aging and NDDs [ 2 , 9 , 10 ]. Neuronal cells hold a broad array of responses to cope with stress conditions including endogenous antioxidant responses (AOR), protein quality control (PQC) systems, and protein degradation pathways [ 11 , 12 , 13 , 14 , 15 ].…”

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“…Nevertheless, abnormal intramolecular interactions may occur that are thermodynamically more stable than the native state, leading to the formation of various species including oligomers, amorphous aggregates, and amyloid fibers [ 12 ]. The proteostasis network blocks such spontaneous interactions during and after translation, which may lead to problems such as Parkinson’s, Alzheimer’s, cardiomyopathy, and amyotrophic lateral sclerosis [ 13 ].…”

“…In addition to correcting the physical structure of proteins, they mediate the solubility of misfolded proteins and prevent their self-association and toxic aggregation. However, the presence of various factors such as stress, mutation, heavy metals, reactive oxygen species, translational deviation or mRNA defect may overshadow cell repair operations and increase the possibility of abnormal intramolecular and/or intermolecular interactions [ 13 , 16 ]. Chaperons typically recognize exposed hydrophobic amino acid residues and unstructured polypeptide backbones in their substrate proteins, which are unifying features of non-native conformations and make hydrophobic and electrostatic interactions with them to prevent (or reverse) misfolding and aggregation [ 16 ].…”