Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

Abstract

A general hallmark of neurological diseases is the loss of redox homeostasis that triggers oxidative damages to biomolecules compromising neuronal function. Under physiological conditions the steady-state concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are finely regulated for proper cellular functions. Reduced surveillance of endogenous antioxidant defenses and/or increased ROS/RNS production leads to oxidative stress with consequent alteration of physiological processes. Neuronal cells are particularly susceptible to ROS/RNS due to their biochemical composition. Overwhelming evidences indicate that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-linked pathways are involved in protective mechanisms against oxidative stress by regulating antioxidant and phase II detoxifying genes. As such, Nrf2 deregulation has been linked to both aging and pathogenesis of many human chronic diseases, including neurodegenerative ones such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis. Nrf2 activity is tightly regulated by a fine balance between positive and negative modulators. A better understanding of the regulatory mechanisms underlying Nrf2 activity could help to develop novel therapeutic interventions to prevent, slow down or possibly reverse various pathological states. To this end, microRNAs (miRs) are attractive candidates because they are linked to intracellular redox status being regulated and, post-transcriptionally, regulating key components of ROS/RNS pathways, including Nrf2.

The expression of miR‐125b in Nrf2‐silenced A549 cells exposed to hyperoxia and its relationship with apoptosis

“…miRNAs are involved in the regulation of intracellular redox and post-transcriptional regulation of key components of the ROS/ reactive nitrogen (RNS) pathway, including Nrf2. 9 Jing Zhou et al 10 showed that H 2 O 2 activated the Nrf2 signalling pathway in a mouse corneal epithelial progenitor cell line (TKE2) and increased the expression of miR-125b.…”

“…Recent studies have shown that miRNAs regulate Nrf2 directly or indirectly, which may be an important mechanism underlying miRNAs involvement in cell differentiation and apoptosis. miRNAs are involved in the regulation of intracellular redox and post‐transcriptional regulation of key components of the ROS/reactive nitrogen (RNS) pathway, including Nrf2 . Jing Zhou et al showed that H 2 O 2 activated the Nrf2 signalling pathway in a mouse corneal epithelial progenitor cell line (TKE2) and increased the expression of miR‐125b.…”

Non-Coding RNAs as Sensors of Oxidative Stress in Neurodegenerative Diseases

“…Nrf2, involved in redox reactions, participates in ER stress-induced apoptosis and together with ATF4 repress miR-106b-25 cluster. It has been shown that the Nrf2/ATF4/miR-106b-25 cluster may be relevant for ALS pathogenesis [244]. In addition, miR-142-5p, that is downregulated in the CSF of ALS patients, has been shown to reduce OS via the upregulation of the Nrf2 signaling pathway [236,245].…”

Why Do the Cosmic Rays Induce Aging?

“…In fact, the DNA damage from ionizing radiation has thus been attributed to the formation of radicals from the radiolysis of water molecules, as will be treated extensively in a later paragraph. More recently, also in light of the progress on understanding radicals as elements of intracellular and intercellular communication (Paladino et al, 2018), more and more weight is being given to biological pathways mediated by mitochondrial oxide-reduction while intermediate metabolic products can lead to oxidation, nitrosylation, and alkylation of DNA (Hekimi et al, 2011). Whatever their origin, ROS are able to induce DNA damage either directly or indirectly by interfering with the activity of the epigenetic regulatory factors and the DDR proteins.…”