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Review
. 2020 Mar 27:2020:5497046.
doi: 10.1155/2020/5497046. eCollection 2020.

Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress

Annika Höhn  1   2 , Antonella Tramutola  3 , Roberta Cascella  4
Affiliations
Review

Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress

Annika Höhn et al. Oxid Med Cell Longev. .

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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Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this paper.

Figures

Figure 1
Figure 1
Proteasomal complexes. 20S and 26S models according to data from X-ray structure analysis [267].
Figure 2
Figure 2
Different types of autophagy in mammalian cells. Macroautophagy requires sequential steps leading to the formation of autophagosomes. After the fusion of an autophagosome with a lysosome, the cargo is degraded and released to the cytosol. Chaperone-mediated autophagy involves the recognition of substrates (mainly abnormal or damaged proteins) with a KFERQ motif, whereas microautophagy involves direct sequestration of cytoplasmic portions into the lysosome. Modified according to [268].
Figure 3
Figure 3
Schematic description of two ubiquitination-like modification systems essential for autophagy: Atg12-Atg5-conjugation and LC3-modification. Details can be found in the text.
Figure 4
Figure 4
Cellular damage induced by oxidative stress: protein oxidation, lipid peroxidation, DNA damage, mitochondrial dysfunction, and perturbation of the endoplasmic reticulum. Cell membrane illustration was used from Servier Medical Art under creative commons license 3.0 (https://smart.servier.com/).
See this image and copyright information in PMC

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