Intersection of H2S and Nrf2 signaling: Therapeutic opportunities for neurodegenerative diseases

Abstract

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), represent a significant global health burden due to their progressive and debilitating nature. While the etiology of these disorders is multifaceted, oxidative stress, resulting from an imbalance between the generation of reactive oxygen species (ROS) and neuronal antioxidant stress responses, has emerged as a pivotal factor in their pathogenesis. Amongst the cellular defense mechanisms counteracting oxidative stress, signaling cascades regulated by the nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) signaling axis, play a crucial role. Nrf2 signaling is modulated at multiple levels and regulates redox homeostasis and other cellular processes such as expression of neuroprotective genes, resolution of neuroinflammation, stimulating mitochondrial bioenergetics, facilitating cellular repair, and proteostasis. In recent years, the gaseous molecule or gasotransmitter, hydrogen sulfide (H₂S), was shown to modulate Nrf2-mediated signaling through processes that include disruption of Keap1-Nrf2 interaction, leading to enhanced Nrf2 activation. This review explores the intricate relationship between hydrogen sulfide and Nrf2-Keap1 signaling, highlighting their potential to counteract neurodegenerative processes. The interplay between H₂S and Nrf2 signaling underscores their potential as endogenous regulators of cellular resilience against neurodegeneration. Understanding how gasotransmitters fine-tune the Nrf2-Keap1 pathway opens up new avenues for therapeutic interventions in these neurodegenerative disorders. By elucidating how gasotransmitters influence Nrf2-mediated responses, we aim to underscore promising therapeutic strategies that target oxidative damage, modulate neuroinflammation, and enhance neuronal survival pathways in neurodegenerative diseases.

Keywords: Alzheimer's disease; Gasotransmitters; Huntington's disease; Neurodegenerative diseases; Nrf2-Keap1 signaling; Parkinson's disease.

Fig. 1

Mechanism of Nrf2 activation by hydrogen sulfide (H₂S) donors through Keap1 persulfidation. Under basal conditions (left panel), Nrf2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1), which facilitates its ubiquitination via the Cul3-RBX1 E3 ligase complex, leading to proteasomal degradation and suppression of its transcriptional activity. In contrast, treatment with H₂S donors (right panel) induces sulfhydration of specific cysteine residues on Keap1, thereby disrupting the Keap1-Nrf2 interaction. This results in the release and stabilization of Nrf2, allowing its accumulation and nuclear translocation. Within the nucleus, Nrf2 heterodimerizes with small Maf proteins and binds to antioxidant response elements (AREs) in the promoter regions of target genes, leading to the transcriptional activation of neuroprotective genes. Created with BioRender.com.

Fig. 2

Multifaceted roles of H₂S and Nrf2 signaling in neurodegenerative disease pathology. H₂S and Nrf2 promote redox homeostasis by enhancing antioxidant defenses, reducing oxidative damage caused by excess ROS. They also stabilize mitochondrial function, improving bioenergetics and preserving cellular integrity. Additionally, Nrf2-H₂S signaling stimulates autophagy, facilitating the clearance of misfolded proteins and cellular debris. These factors further contribute to epigenetic regulation, modulating gene expression to enhance cellular resilience. Conversely, they inhibit tau hyperphosphorylation by suppressing GSK3β activity, preventing toxic tau accumulation and aggregation. Nrf2 and H₂S also prevent β-amyloid plaque formation, reducing its pathological burden. Their anti-inflammatory properties mitigate neuroinflammation by dampening microglial activation and inflammatory cytokine release, thereby protecting neurons from inflammation-induced damage. Furthermore, Nrf2-H₂S signaling prevents cellular senescence, delaying age-related deterioration and sustaining neuronal function. Created with BioRender.com.