Toxic Tango in Parkinson's Disease: A dance between αSyn and iron import, export and speciation

The intricate interplay between brain iron homeostasis and pathological α-Synuclein (αSyn) in Parkinson's Disease (PD) is still unclear. αSyn is the primary protein involved in disease progression and promotes cytotoxicity by impairing dopamine synthesis, mitochondrial dysfunction and disrupts brain iron homeostasis. Iron has further revealed to induce αSyn aggregation however, the exact mechanism of interaction between iron and αSyn is uncertain. Many studies have demonstrated an imbalance of iron homeostasis in PD pathogenesis, including macroautophagy related to αSyn aggregate and accumulated ferritin degradation. Inducible ferritinophagy has been suggested as a possible therapeutic to combat raised ferritin levels and reinstate iron homeostasis however this may lead to increased ferroptosis. Despite limited knowledge of ferritinophagy induced ferroptosis in PD there is a possible link to neurodegeneration. This review aims to summarise the current understanding of the chemical interactions between iron and αSyn and possible binding affinities in biologically relevant models, while further highlighting αSyn's pathological role in neurodegeneration and aberrant iron homeostasis. Developing knowledge surrounding the complex interactions between αSyn and iron in PD will aid in possible therapeutic strategies to combat PD disease progression.