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

Abstract

Oxidative stress (OS) results from an imbalance between the production of reactive oxygen species and the cellular antioxidant capacity. OS plays a central role in neurodegenerative diseases, where the progressive accumulation of reactive oxygen species induces mitochondrial dysfunction, protein aggregation and inflammation. Regulatory non-protein-coding RNAs (ncRNAs) are essential transcriptional and post-transcriptional gene expression controllers, showing a highly regulated expression in space (cell types), time (developmental and ageing processes) and response to specific stimuli. These dynamic changes shape signaling pathways that are critical for the developmental processes of the nervous system and brain cell homeostasis. Diverse classes of ncRNAs have been involved in the cell response to OS and have been targeted in therapeutic designs. The perturbed expression of ncRNAs has been shown in human neurodegenerative diseases, with these changes contributing to pathogenic mechanisms, including OS and associated toxicity. In the present review, we summarize existing literature linking OS, neurodegeneration and ncRNA function. We provide evidences for the central role of OS in age-related neurodegenerative conditions, recapitulating the main types of regulatory ncRNAs with roles in the normal function of the nervous system and summarizing up-to-date information on ncRNA deregulation with a direct impact on OS associated with major neurodegenerative conditions.

Oxidative Stress and the Neurovascular Unit

“…Noncoding RNAs are implicated in a wide variety of cellular processes, as well as in many disease conditions [ 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 ] in which the oxidative stress alters ROS homeostasis. Oxidative stress induces the expression of several transcription factors such as NFκB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, and Nrf2 that, in turn, activate the expression of hundreds of genes which are associated with growth factors signaling, immune responses, and cell cycle transition.…”

Roles of physical exercise in neurodegeneration: reversal of epigenetic clock

“…Neuronal death, whether apoptosis or necrosis, is caused by a variety of mechanisms related to DNAm. Studies on genetic and environmental factors in neurodegenerative diseases have shown that the imbalance between oxidative and antioxidant systems, caused by the increase in reactive oxygen species (ROS) and the deficiency of antioxidant capacity, is the main contributor to oxidative stress [ 113 ], which ultimately leads to neuronal death [ 113 , 114 ]. Treadmill exercise can reverse the related neuronal loss by preventing oxidative damage of DNA [ 115 ].…”

Free radical biology in neurological manifestations: mechanisms to therapeutics interventions

“…MicroRNAs or miRNAs are short (20-24 nucleotides) regulatory ncRNAs that were first discovered in C. elegans in 1993 (Lee et al 1993). They are one of the major negative posttranscriptional modulators and act by imperfect complementary base pairing with mRNA, resulting in recruitment of various RNA degrading factors or protein translation inhibition (Gámez-Valero et al 2020). They modulate the cellular response to FR toxicity inducing inflammation, mitochondrial impairment, aberrant protein and lipid modifications, nucleic acid damage, and gene expression changes (Tönnies and Trushina 2017).…”