Summary

There is currently no effective neuroprotective therapy to reduce the progression of Parkinson’s disease (PD). Iron enrichment in the substantia nigra pars compacta (SNc) reflects an involvement in dopamine metabolism and fuelling neuronal activity. In PD, a progressive damage of the SNc is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At the molecular cell level, mutations in α-synuclein cause alterations in dopamine and iron transport. Those alterations might trigger an iron-dependent cell death pathway, ferroptosis, offering new prospects for treatment. The application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool to identify early stages of nigral pathology. In mammalian models, chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage. However, iron chelation regimens that have proven to be effective in treating systemic siderosis are not clinically suitable for PD patients, as those may develop iatrogenic iron depletion and ensuing anaemia. Moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred either to higher-affinity acceptors in cells or to extracellular transferrin. Promising preclinical and clinical proof of principle trials have led to a current large randomized clinical trial that aims to demonstrate the efficacy of conservative iron chelation. As one of the first non-dopaminergic disease-modifying strategies in PD, outcomes could provide a first-in-class treatment strategy to slow disease progression.