Therapeutic Inhibition of Mutant MnSOD    Using Aptamers to Attenuate Mitochondrial Oxidative Stress in Depression

Abstract

Depression imposes a substantial burden not only on affected individuals but also on society at large and is characterized by reduced productivity in daily activities, increased healthcare costs, diminished social engagement, and a heightened risk of comorbid health conditions, all impairing an individual’s ability to lead a healthy, functional, and fulfilling life. Manganese superoxide dismutase (MnSOD) is  an essential mitochondrial enzyme that acts as a protective antioxidant by neutralizing reactive oxygen species (ROS). Mutated forms of MnSOD compromise mitochondrial antioxidant defenses, leading to oxidative stress, neurodegeneration, and mitochondrial dysfunction. Therefore, inhibiting the mutated form of MnSOD could serve as a potential strategy to limit mutation-induced neuroinflammation, ulti- mately reducing the risk of depression. Aptamers are single-stranded nucleotide molecules that bind specifically to target proteins. We hypothesize that Aptamer 1 is the most suitable candidate for mitigat- ing depression by binding to and inhibiting the MnSOD protein. Computational tools evaluated various aptamers’ binding affinity and efficiency to MnSOD. Protein modeling was conducted using AlphaFold3; aptamer structures were modeled using UNAfold and FARFAR2; and aptamer-protein docking was per- formed using HDOCK. PLIP was used to analyze the molecular interactions between the aptamers and MnSOD. Among the tested aptamers, Aptamer 1 demonstrated the highest number of hydrogen bonds with MnSOD, suggesting superior binding efficiency. As MnSOD is implicated in neuroinflammation and elevated cortisol levels—both contributing factors to depression—Aptamer 1 may offer therapeutic potential by reducing MnSOD-related oxidative stress. This study supports the development of novel aptamer-based therapeutics for depression and related neuroinflammatory conditions.