Unveiling the role of trace elements in modulating inflammatory and oxidative pathways in CAG repeat–driven spinocerebellar ataxia

Spinocerebellar ataxias are genetically inherited neurodegenerative disorders, primarily caused by CAG trinucleotide repeat expansions in genes. While these genetic mutations initiate disease onset, increasing evidence suggests that systemic factors, particularly trace element imbalance, oxidative stress, and immune dysregulation, play critical roles in disease progression. In this study, peripheral blood samples from genetically confirmed SCA patients (n = 15) and age- and sex-matched healthy controls (n = 18) were analyzed. Atomic Absorption Spectroscopy revealed significant alterations in plasma concentrations of both essential and toxic trace elements, suggesting their involvement in neurotoxicity, redox imbalance, and inflammation. To explore these links, oxidative stress markers, including malondialdehyde, superoxide dismutase, and glutathione peroxidase, as well as cytokines such as interleukin-6, interleukin-4, and interleukin-10, were quantified using ELISA. Receiver operating characteristic analysis demonstrated high diagnostic accuracy of these markers, particularly GPx and IL-10. A strong interconnection was observed among trace element dysregulation, oxidative stress, and inflammatory responses, indicating a synergistic role in exacerbating neurodegeneration. Molecular docking revealed that abnormal trace element levels may impair antioxidant enzyme function by disrupting metal-binding interactions, offering mechanistic insight into enzymatic dysfunction. Bioinformatics analyses, including functional enrichment and protein–protein interaction mapping, identified significant associations with mitochondrial dysfunction, reactive oxygen species metabolism, and cytokine signaling pathways. These findings suggest that SCA pathogenesis is not driven by genetic mutation alone. The combined effects of trace element imbalance, oxidative stress, and inflammation contribute to a complex pathogenic network, reinforcing the importance of targeting both genetic and systemic factors in therapeutic strategies.