When It Comes to an End: Oxidative Stress Crosstalk with Protein Aggregation and Neuroinflammation Induce Neurodegeneration

Abstract

Neurodegenerative diseases are characterized by a progressive loss of neurons in the brain or spinal cord that leads to a loss of function of the affected areas. The lack of effective treatments and the ever-increasing life expectancy is raising the number of individuals affected, having a tremendous social and economic impact. The brain is particularly vulnerable to oxidative damage given the high energy demand, low levels of antioxidant defenses, and high levels of metal ions. Driven by age-related changes, neurodegeneration is characterized by increased oxidative stress leading to irreversible neuronal damage, followed by cell death. Nevertheless, neurodegenerative diseases are known as complex pathologies where several mechanisms drive neuronal death. Herein we discuss the interplay among oxidative stress, proteinopathy, and neuroinflammation at the early stages of neurodegenerative diseases. Finally, we discuss the use of the Nrf2-ARE pathway as a potential therapeutic strategy based on these molecular mechanisms to develop transformative medicines.

Keywords: Nrf2-ARE pathway; neurodegenerative diseases; neuroinflammation; oxidative stress; protein aggregates; reactive species; redox signaling.

Figure 1

Principal RS sources and sinks. Transmembrane NADPH oxidases (NOX) and the mitochondrial ETC generate O₂^•− that can be converted to ONOO⁻ in presence of NO, or can be converted to H₂O₂ by superoxide dismutase (SOD). Peroxisomes, endoplasmic reticulum (ER), and mitochondrial monoamine oxidase (MAO) also contribute to H₂O₂ production. Catalase (CAT), glutathione peroxidase (GPx), and peroxiredoxin (Prx) remove H₂O₂; otherwise, metal-catalyzed Fenton reactions generate •OH that oxidizes cellular biomolecules.

Figure 2

Cysteine redox modification by H₂O₂. Low H₂O₂ concentrations lead to sulfenates (SO⁻) formation that can form disulfide (SS) or glutathionylated proteins (SSG), and sulfinates (SO₂⁻). These modifications can be reversed by thioredoxins (Trx), glutaredoxins (Grx) or sulfiredoxins (Srx). Under OS, the formation of sulfonate (SO₃⁻) leads to irreversible damage. Likewise, amino acid oxidation by •OH or ONOO⁻ forms protein carbonyls and 3-nitrotyrosine residues that alter the protein function.

Figure 3

Cellular proteostasis is lost under OS. OS promotes protein misfolding and hydrophobic core exposure, leading to the formation of protein aggregates. Protein control systems, ubiquitin-proteasome system (UPS), chaperone-mediated autophagy (CMA), and macroautophagy (autophagy) are harnessed by OS, favoring protein aggregation. In addition, protein aggregates trap metal ions to produce RS-impairing mitophagy, leading to the accumulation of dysfunctional mitochondria. Also, the ER is damaged by OS, further promoting protein misfolding.

Figure 4

OS triggers chronic neuroinflammation, promoting neurodegeneration. Glial cells express TLR and NLR that sense harmful agents. Glial activation through TLR triggers the NF-κB signaling pathway and NLR like ligand-gated ionotropic purinergic receptor (P2X) that triggers NLRP3 signaling, promoting cytokine release, and also chemokines and RS (from NOX and iNOS enzymes). In healthy CNS, glial cells resolve the inflammatory response; in NDDs, the presence of protein aggregates and factors released from dying neurons leads to a sustained glial activation that contributes to neuronal demise.

Figure 5

The Nrf2-ARE pathway provides neuroprotection in multiple ways. The activation of the Nrf2-ARE pathway increases the expression of antioxidant enzymes and GSH levels, thus preventing the damage to biomolecules, mitochondrial dysfunction, and neuronal apoptosis. Nrf2-ARE pathway upregulation prevents OS-driven protein misfolding and aggregation, and also stimulates the UPS and autophagy systems to control the cellular proteostasis. Additionally, the Nrf2-ARE pathway exerts anti-neuroinflammatory properties, induces the expression of the anti-inflammatory enzyme HO-1, interferes with the transcription of the inflammatory NF-κB pathway, and down-regulates NOX and iNOS-derived RS. The antioxidant and anti-neuroinflammatory effect and protein homeostasis regulation mediated by the Nrf2-ARE pathway prevents neurodegeneration.