Fig. 3

Iron dysregulation among different cells occurs in the state of PD. The increased iron level and decreased ferritin level have been found in the CSF under the state of PD. The increased permeability of BBB facilitates the import of iron through TfR1 by microvascular endothelial cells, which is then released into the brain through FPN1. Once iron crosses the BBB, astrocytes absorb it and mediate its transfer to neurons. Astrocytes have shown a neuroprotective role in PD through the secretion of hepcidin and ferritin, which not only decreases brain iron load by regulating FPN1 on microvascular endothelial cells but also controls iron import by regulating iron-related proteins. With exposure to α-synuclein, iron, or neurotoxins, astrocytes also exhibit an iron-releasing phenotype that is detrimental to neighboring neurons. Microglia are the most susceptible neuronal cells to ferroptosis. Upon stimulation, activated microglia release proinflammatory factors, iron, as well as α-synuclein, which interact and exacerbate dopaminergic neurotoxicity. On the other hand, activated microglia can synthesize lactoferrin and protect vulnerable dopaminergic neurons. Oligodendrocytes harbor the highest concentration of iron in the CNS, which can secrete a ferritin heavy chain and protect dopaminergic neurons from oxidative stress. Abnormal import and export of iron-mediated by iron-related proteins cause iron deposition in nigral dopaminergic neurons, resulting in the loss of dopaminergic neurons in PD. This figure was created with BioRender.com/f23j195