Metal Ions and Protein Aggregation: Unraveling Molecular Interactions and Theranostic Prospects in Proteinopathies

Protein aggregation is a pathological process associated with several human diseases termed proteinopathies, including neurodegenerative and metabolic disorders such as Alzheimer's disease, Parkinson's disease, type II diabetes, amyotrophic lateral sclerosis, and Huntington's disease. In these conditions, specific proteins misfold and accumulate into insoluble aggregates, disrupting normal cellular function and contributing to disease progression. Many studies have investigated the molecular mechanisms that underlie the aggregation pathways, the structure of aggregates, such as oligomeric intermediates and fibrils, and their cellular toxicity. Studies have also investigated the effects of cofactors like metals, lipids, other amyloid proteins, and small molecules. Recent research has increasingly emphasized the critical roles of metal ions such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) in amyloid aggregation and toxicity. Alterations in metal ion transport, binding, or redox activity have been linked to the onset and progression of several amyloid-associated diseases. These metal ions can interact directly with amyloidogenic proteins, influencing their structural conformation, aggregation kinetics, and propensity to form toxic oligomers. This review aims to advance our understanding of how the regulation of metal ions within cells and their dysfunction contribute to the accumulation of harmful proteins, which is a key factor in proteinopathies. By examining the interactions between metal ions and key amyloidogenic proteins─including amyloid-β (Aβ), α-synuclein, tau, superoxide dismutase 1 (SOD1), human islet amyloid polypeptide (hIAPP), and insulin─we highlight both common and unique pathways through which metal ions influence protein aggregation. Additionally, this review explores the impact of metal ions on protein clearance mechanisms, such as autophagy and the ubiquitin-proteasome system, as well as emerging theranostic strategies. These include metal chelation therapies, metal-based imaging agents, and multifunctional compounds designed to restore metal balance while preventing aggregation and toxicity. By integrating biochemical, cellular, and therapeutic insights, this review contributes to a deeper understanding of the metallobiology of proteinopathies and supports the development of novel diagnostic and treatment approaches targeting metal-protein interactions.