Metal Ions: Key Modulators Of Neurodegenerative Diseases

Metal ions are essential brain micronutrients, and iron, copper, zinc, and manganese support neurotransmission, cellular metabolism, antioxidant defense, and enzyme cofactor functions. Metal dyshomeostasis can promote neuronal injury through oxidative stress, protein aggregation, mitochondrial dysfunction, ferroptosis, cuproptosis, cellular senescence, and neuroinflammation. Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and prion-like diseases show abnormal metal homeostasis linked to amyloid-β, tau, α-synuclein, SOD1, and prion-like protein aggregation. Mechanistically, redox-active iron, copper, and manganese can drive reactive oxygen species formation, while redox-inactive zinc contributes to structural, catalytic, and signaling functions; metal imbalance can also affect NF-κB, MAPK, and Nrf2 pathways. Disease applications focus on copper, iron, and zinc interactions with amyloid-β and tau pathology in Alzheimer’s disease; iron and manganese abnormalities, oxidative damage, and dopaminergic neuronal loss in Parkinson’s disease; and copper-SOD1 biology in ALS. Drug discovery strategies include metal chelators, metal-homeostasis modulators, antioxidant approaches, and mitochondrial metal-homeostasis interventions. Current gaps include limited region-specific human brain metal measurements, incomplete evidence on metal oxidation states and subcellular localization, inconsistent clinical performance of chelation therapy, and unresolved links among disease stage, genetic background, and environmental exposure. Future experiments should integrate metallomics, brain-region imaging, protein aggregation models, mitochondrial assays, and clinical biomarkers to separate protective metal signaling from pathogenic metal toxicity^{[1][2][3][4][5][6][7][8]}.