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Review
. 2019 Aug 9;20(16):3896.
doi: 10.3390/ijms20163896.

Causative Links between Protein Aggregation and Oxidative Stress: A Review

Elise Lévy  1   2 , Nadine El Banna  2 , Dorothée Baïlle  2 , Amélie Heneman-Masurel  2 , Sandrine Truchet  1 , Human Rezaei  1 , Meng-Er Huang  2 , Vincent Béringue  1 , Davy Martin  3 , Laurence Vernis  4
Affiliations
Review

Causative Links between Protein Aggregation and Oxidative Stress: A Review

Elise Lévy et al. Int J Mol Sci. .

Abstract

Compelling evidence supports a tight link between oxidative stress and protein aggregation processes, which are noticeably involved in the development of proteinopathies, such as Alzheimer's disease, Parkinson's disease, and prion disease. The literature is tremendously rich in studies that establish a functional link between both processes, revealing that oxidative stress can be either causative, or consecutive, to protein aggregation. Because oxidative stress monitoring is highly challenging and may often lead to artefactual results, cutting-edge technical tools have been developed recently in the redox field, improving the ability to measure oxidative perturbations in biological systems. This review aims at providing an update of the previously known functional links between oxidative stress and protein aggregation, thereby revisiting the long-established relationship between both processes.

Keywords: oxidative stress; protein aggregation; proteinopathy; redox.

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Conflict of interest statement

The authors declare no conflict of interest. The funding sponsors had no role in the writing of the manuscript.

Figures

Figure 1
Figure 1
General picture of the protein aggregation process. The unfolded and misfolded monomer structures are aggregation prone. Folded monomers can also aggregate from native-like conformations without going through the unfolded step. The association of several monomers gives rise to oligomeric aggregates with low molecular weight. The addition of oligomers in an ordered manner permits the growth of oligomers to protofibrils and mature fibrils. Amorphous aggregates can arise from the precipitation of monomers or oligomers, possibly leading to protein inclusions.
Figure 2
Figure 2
Amyloid Precursor Protein (APP) processing. (A) Cleavage of APP occurs through two pathways. The non-amyloidogenic pathway (grey, left) involves two cleavages by α- and γ-secretases and produces a long APPα fragment, which is secreted. C-Terminal Fragment (CTF)83, 3-kd peptide, (P3), and APP intracellular domain (AICD) fragments are also released. In parallel, the amyloidogenic pathway (pink, right) involves two cleavages by β- and γ-secretases, producing a long APPβ, which is secreted. CTF99, AICD, and Aβ fragments are also produced. In pathological conditions, Aβ peptides accumulate and can ultimately aggregate and form oligomers and fibrils that are toxic for the cells (adapted from [36]). (B) Schematic representation of the APPα fragment, produced after cleavage of the APP by α-secretase. The E2 domain is highlighted (green). (C) Zooming in on the four cysteine residues involved in the tetra-His M1 site, included in the E2 domain. The Cu cation is pictured as a red ball (adapted from [37] with permission).
Figure 3
Figure 3
General diagram showing the regulation of protein aggregation. Arrows indicate the activation relationship, and blunt-ended arrows indicate the repression relationship. References supporting this diagram within this review are as follows: 1: [20,21,24,28,31,32,35,41,42,43,44,45,46,47,49,50]; 2: [58,61]; 3: [57]; 4: [62,63]; 5: [51,52,53,54,55]; 6: [80]; 7: [74,75,76,77,78,79,80]; 8: [64,65,66,67,68,69,70,71,72,73,82,83,84]; 9: [47,88,89,90,91,92,93,94,95,96,97,98,99]; 10: [100,101,102,103,104,105,106,107].
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References

    1. Hipp M.S., Park S.H., Hartl F.U. Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends Cell Biol. 2014;24:506–514. doi: 10.1016/j.tcb.2014.05.003. - DOI - PubMed
    1. Li J., Labbadia J., Morimoto R.I. Rethinking HSF1 in Stress, Development, and Organismal Health. Trends Cell Biol. 2017;27:895–905. doi: 10.1016/j.tcb.2017.08.002. - DOI - PMC - PubMed
    1. Scherzinger E., Lurz R., Turmaine M., Mangiarini L., Hollenbach B., Hasenbank R., Bates G.P., Davies S.W., Lehrach H., Wanker E.E. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell. 1997;90:549–558. doi: 10.1016/S0092-8674(00)80514-0. - DOI - PubMed
    1. Scherzinger E., Sittler A., Schweiger K., Heiser V., Lurz R., Hasenbank R., Bates G.P., Lehrach H., Wanker E.E. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington’s disease pathology. Proc. Natl. Acad. Sci. USA. 1999;96:4604–4609. doi: 10.1073/pnas.96.8.4604. - DOI - PMC - PubMed
    1. Beerten J., Schymkowitz J., Rousseau F. Aggregation prone regions and gatekeeping residues in protein sequences. Curr. Top. Med. Chem. 2012;12:2470–2478. doi: 10.2174/1568026611212220003. - DOI - PubMed

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