Oxidative genomic or genotoxic stress in neurodegeneration: Mechanisms and therapeutic avenues

Neurons are especially vulnerable because of their high metabolic activity and limited ability to repair damaged DNA. Oxidative genotoxic stress (OGS), which arises from the buildup of short-lived, highly reactive molecules called reactive oxygen species (ROS), can damage neuronal DNA and compromise antioxidant defense mechanisms in neurons. OGS induces considerable forms of DNA damage, including genomic instability, DNA strand breaks (single or double), DNA base modifications such as 8-oxoguanine, and epigenetic changes, leading to compromised neuronal functions. Moreover, OGS is a silent player in mitochondrial DNA damage and mitochondrial dysfunction. Therefore, ROS-mediated OGS is pivotal for initiating and advancing several neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinsonism (PD), and Huntington's disease (HD). However, there is a significant gap in deciphering the molecular pathways involved in OGS-mediated development of neurodegenerative diseases. Hence, this study focused on the molecular mechanisms by which OGS causes neurodegeneration, with a focus on the contributions of neuroinflammation, mitochondrial dysfunction, and defective DNA repair pathways. Additionally, new therapeutic approaches, such as mitochondrial-targeted medications, antioxidant therapies, gene editing tools such as CRISPR/Cas9, and biomarkers for the early diagnosis of these oxidative diseases, have been assessed. A thorough comprehension of these processes opens exciting possibilities for focused treatments in neurodegenerative illnesses.