MECHANISTIC STUDY OF METAL ION HOMEOSTASIS AND ITS DISRUPTION IN NEURODEGENERATIVE DISEASES

Abstract

Disruption in metal ion homeostasis has emerged as a critical factor in the onset and progression of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). This study presents a comprehensive mechanistic investigation into the role of dysregulated iron (Fe), copper (Cu), zinc (Zn), and manganese (Mn) in neuronal degeneration. Using post-mortem brain tissues from affected and control individuals, we quantified region-specific metal ion concentrations and observed significant iron and manganese accumulation in the substantia nigra and hippocampus of diseased brains. Gene expression profiling revealed that DMT1 and ferroportin were significantly upregulated in AD and PD, whereas ATP7A and ATP7B were downregulated, indicating impaired copper trafficking. Oxidative stress markers—including reactive oxygen species (ROS), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE)—were markedly elevated in all disease groups, with ROS levels nearly doubling in AD compared to controls. Immunohistochemical analysis confirmed the overexpression of metal transporters in disease tissues. Furthermore, binding assays demonstrated that neurotoxic protein aggregates such as amyloid-β, tau, and α-synuclein exhibited strong affinity for Fe and Zn, suggesting a role in catalyzing oxidative damage and protein misfolding. Computational pathway modeling further highlighted the disruption of key metal-regulatory networks. Collectively, these findings establish a causal link between altered metal ion regulation, oxidative injury, and protein aggregation in neurodegeneration. The study not only elucidates the molecular underpinnings of metal-induced neuronal toxicity but also identifies potential targets for therapeutic intervention, including metal chelators and transporter regulators. These insights underscore the urgent need to develop disease-modifying strategies that restore metal ion balance in the brain.