Reimagining the contribution of iron in Parkinson's disease.

Parkinson's Disease (PD) is the fastest-growing neurodegenerative disease globally, with prevalence increasing more rapidly than Alzheimer's disease. PD pathogenesis has traditionally been framed around iron accumulation in the substantia nigra (SN), resulting in oxidative injury to vulnerable dopaminergic neurons. However, excess iron alone does not readily explain the temporal emergence of dopaminergic susceptibility across the lifespan. Epidemiological and clinical studies consistently show that iron deficiency often precedes PD diagnosis by more than a decade, suggesting that early iron dysregulation establishes a prodromal metabolic state that destabilizes the nigrostriatal system. Here we propose a dynamic two-phase framework in which iron deficiency establishes a latent vulnerability state characterized by impaired iron-dependent enzymatic activity, diminished ferritin buffering, weakened mitochondrial function, and reduced antioxidant defenses. In this primed context, subsequent increases in dopaminergic flux during L-DOPA therapy may amplify oxidative stress by elevating cytosolic dopamine, perturbing iron handling, and promoting dopamine iron redox chemistry that generates quinones and reactive oxygen species (ROS). Transitions in iron availability including iron supplementation, may further aggravate this process but are not required for its initiation. By reframing PD as a disorder shaped by dynamic changes in iron availability interacting with dopaminergic demand, this review integrates evidence across iron biology, dopaminergic signaling, oxidative stress, and neuroinflammation to propose a mechanistically novel model of PD pathogenesis. This conceptual shift highlights new opportunities for risk stratification, biomarker development, and refinement of dopaminergic therapy within iron dysregulated states.