Oxidative Stress in Age-Related Neurodegenerative Diseases: An Overview of Recent Tools and Findings

Abstract

Reactive oxygen species (ROS) have been described to induce a broad range of redox-dependent signaling reactions in physiological conditions. Nevertheless, an excessive accumulation of ROS leads to oxidative stress, which was traditionally considered as detrimental for cells and organisms, due to the oxidative damage they cause to biomolecules. During ageing, elevated ROS levels result in the accumulation of damaged proteins, which may exhibit altered enzymatic function or physical properties (e.g., aggregation propensity). Emerging evidence also highlights the relationship between oxidative stress and age-related pathologies, such as protein misfolding-based neurodegenerative diseases (e.g., Parkinson’s (PD), Alzheimer’s (AD) and Huntington’s (HD) diseases). In this review we aim to introduce the role of oxidative stress in physiology and pathology and then focus on the state-of-the-art techniques available to detect and quantify ROS and oxidized proteins in live cells and in vivo, providing a guide to those aiming to characterize the role of oxidative stress in ageing and neurodegenerative diseases. Lastly, we discuss recently published data on the role of oxidative stress in neurological disorders.

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“…Free radicals, reactive metabolites, or ROS are classified as oxidative stress when they produce more free radicals than are eliminated by protective mechanisms, including antioxidants. As a result of this imbalance, important biomolecules and cells are damaged, possibly resulting in adverse effects on the entire body [ 22 ]. In response to changes in intra- and extracellular environments, reactive oxygen species produced by normal cellular metabolism can stimulate signaling pathways in animal cells [ 23 ].…”

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“…Persistent OS can lead to the development of various chronic diseases, including aging and degenerative diseases [ 9 ]. Indeed, high levels of OS are often observed in many patients diagnosed with NDDs [ 10 , 12 , 19 ], but it is currently unknown whether OS is a driving force or a consequence that further exacerbates the disease [ 25 ].…”

“…Lipids are highly susceptible to free radical attacks and undergo lipid peroxidation, proteins undergo carbonylation and nitration, and nucleic acids are oxidized [ 6 , 19 ]. These processes have complex effects on mitochondria, metal metabolism, and glial cells, causing neuroinflammation and triggering various forms of programmed cell death such as apoptosis, parthanatos, and ferroptosis [ 19 , 25 ].…”

“…Oxidative damage results in a variety of oxidative modifications to proteins, as multiple amino acid residues are amenable to oxidation. These modifications can alter cellular function by regulating the stability, activity, subcellular localization, or protein–protein interaction of oxidized proteins [ 25 ]. The most important result of protein oxidation is the formation of large protein aggregates, the accumulation of which in cells leads to toxicity.…”

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“…Mitochondrial oxidative stress also showed close correlation to production and aggregation of disordered proteins (including αsynuclein, Aβ and tau protein). High level of mitochondrialgenerated ROS created deleterious modifications environment for normal proteins, lipids, RNA and DNA which exacerbated AD and PD pathology (Korovesis et al, 2023). In AD models, CCH is the precondition of Aβ aggregation.…”