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Review
. 2020 Jun 30;10(7):101.
doi: 10.3390/life10070101.

Interaction of Oxidative Stress and Misfolded Proteins in the Mechanism of Neurodegeneration

Andrey Y Abramov  1   2 , Elena V Potapova  2 , Viktor V Dremin  2   3 , Andrey V Dunaev  2
Affiliations
Review

Interaction of Oxidative Stress and Misfolded Proteins in the Mechanism of Neurodegeneration

Andrey Y Abramov et al. Life (Basel). .

Abstract

Aggregation of the misfolded proteins β-amyloid, tau, huntingtin, and α-synuclein is one of the most important steps in the pathology underlying a wide spectrum of neurodegenerative disorders, including the two most common ones-Alzheimer's and Parkinson's disease. Activity and toxicity of these proteins depends on the stage and form of aggregates. Excessive production of free radicals, including reactive oxygen species which lead to oxidative stress, is proven to be involved in the mechanism of pathology in most of neurodegenerative disorders. Both reactive oxygen species and misfolded proteins play a physiological role in the brain, and only deregulation in redox state and aggregation of the proteins leads to pathology. Here, we review the role of misfolded proteins in the activation of ROS production from various sources in neurons and glia. We discuss if free radicals can influence structural changes of the key toxic intermediates and describe the putative mechanisms by which oxidative stress and oligomers may cause neuronal death.

Keywords: mutant huntingtin protein; neurodegeneration; oxidative stress; reactive oxygen species; tau protein; α-synuclein; β-amyloid.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Effect of oligomeric α-synuclein on the redox balance in neurons. α-Synuclein-induced reactive oxygen species (ROS) lead to decreased endogenous antioxidant (GSH), lipid peroxidation, and oxidation. Although oligomeric α-synuclein has no effect on ROS production in mitochondria, α-synuclein produced ROS oxidase mitochondrial proteins including subunits of F1-F0-ATPase. In combination with calcium overload, it induces mitochondrial permeability transition pore (mPTP) opening and cell death.
Figure 2
Figure 2
Phosphorylated tau forms a channel on the neuronal membrane and induces a calcium signal which activates ROS production in NADPH oxidase. Tau aggregates inhibit mitochondrial respiration and induce ROS overproduction in this organelle.
Figure 3
Figure 3
Effect of β-amyloid on redox homeostasis and mitochondrial metabolism of astrocytes.
See this image and copyright information in PMC

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