Beyond a Single Mechanism: The iron-ROS-lipid Peroxidation Axis as a Central Driver of Prodromal Parkinson's Disease

Neurodegeneration in Parkinson's disease (PD) begins subtly many years before motor symptoms appear. The primary pathological processes involve abnormal aggregation and spread of α-synuclein (α-syn), ongoing glial-mediated neuroinflammation, and disrupted brain iron balance. We suggest that a positive feedback loop involving iron-ROS-lipid peroxidation plays a crucial role in connecting these events and propelling the early stages of PD. Iron overload induces lipid peroxidation through the Fenton reaction, generating products like 4-HNE. These byproducts not only modify α-syn structure but also act as signals that trigger the microglial NLRP3 inflammasome. Additionally, pathological α-syn prompts glial cells to release exosomes containing harmful proteins and oxidized lipids, facilitating the spread of ferroptosis stress between cells and brain regions. This mechanism amplifies damage from single neurons to the entire neural network. This comprehensive framework clarifies the intricate interplay among α-syn pathology, neuroinflammation, and iron imbalance in early PD stages, highlighting ferroptosis as a key driver of disease progression.