Iron Brain Menace: The Involvement of Ferroptosis in Parkinson Disease

Abstract

Parkinson disease (PD) is the second-most common neurodegenerative disease. The characteristic pathology of progressive dopaminergic neuronal loss in people with PD is associated with iron accumulation and is suggested to be driven in part by the novel cell death pathway, ferroptosis. A unique modality of cell death, ferroptosis is mediated by iron-dependent phospholipid peroxidation. The mechanisms of ferroptosis inhibitors enhance antioxidative capacity to counter the oxidative stress from lipid peroxidation, such as through the system x_c^-/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis and the coenzyme Q10 (CoQ10)/FSP1 pathway. Another means to reduce ferroptosis is with iron chelators. To date, there is no disease-modifying therapy to cure or slow PD progression, and a recent topic of research seeks to intervene with the development of PD via regulation of ferroptosis. In this review, we provide a discussion of different cell death pathways, the molecular mechanisms of ferroptosis, the role of ferroptosis in blood-brain barrier damage, updates on PD studies in ferroptosis, and the latest progress of pharmacological agents targeting ferroptosis for the intervention of PD in clinical trials.

Keywords: CoQ10; FSP1; GPX4; Parkinson disease; ferroptosis; glutathione; iron metabolism; lipid peroxidation; lipoxygenase; system xc−.

Figure 1

Regulatory pathways of ferroptosis. The iron metabolism (left) includes the endosomal uptake of ferritin-bound Fe³⁺, Fe³⁺ conversion to Fe²⁺ via STEAP proteins, Fe²⁺ release through the transporters DMT1 and ZIP8/14, and Fe²⁺ distribution to different intracellular regions via the chaperones, including PCBP1 and PCBP2. Iron is delivered to the labile iron pool, imported into the mitochondria, stored in ferritin, etc. In low-iron situations, the degradation of ferritin through ferritinophagy occurs and releases the ferritin-bound iron into the cytoplasm. In the case of excess iron, the iron is exported by ferroportin. The mitochondrial ETC generate O2—which is reduced to H₂O₂ by the antioxidant SOD. The H₂O₂ under the catalysis of Fe²⁺ from the labile iron pool participates in the Fenton reaction, creating hydroxyl radicals, which further activates lipid peroxidation, leading to ferroptosis. The system x_c⁻/GSH/GPX4 axis (right) exerts antioxidative effects to prevent ferroptosis. Cystine is transported into the cell by system x_c⁻ and then converted to cysteine, which is a key component of GSH. The reducing activity of GSH keeps GPX4 in its reduced state to maintain the antioxidative abilities of GPX4. GPX4 can directly inhibit lipid peroxidation, therefore inhibiting ferroptosis. Inducers of ferroptosis inhibit system x_c⁻, such as erastin and glutamate, or inhibit GPX4, such as RSL3. Inhibitors of ferroptosis include iron chelators, such as deferoxamine, and lipid peroxidation inhibitors, such as CoQ10, ferrostatin-1, and liproxstatin-1.

Figure 2

The mechanisms of lipid peroxidation and chemical formula. Lipid peroxidation involves two pathways, the non-enzymatic pathway and the enzymatic pathway. The non-enzymatic pathway includes three steps: initiation, propagation, and termination. In the initiation step, membrane phospholipids are targeted by radicals, such as the hydroxyl radicals, from the Fenton reaction and form lipid radicals. In the propagation step, O₂ added to the lipid radical forms the lipid peroxyl radical and the addition of phospholipid generates lipid hydroperoxide. This forms a loop, creating new lipid peroxyl radicals, and eventually can lead to ferroptosis. In the termination step, antioxidants, such as the system x_c⁻/GSH/GPX4 axis and the CoQ10/FSP1 pathway exert, antioxidative effects. GPX4 can directly convert lipid hydroperoxide to lipid alcohol. In the enzymatic pathway, the PUFA is ligated to CoA under ACSL4. LPCAT3 catalyzes PUFA–CoA esterification into PE–PUFA, and the PUFA forms a side chain of the phospholipid. Under the enzyme LOX and the presence of Fe²⁺, PE–PUFA forms toxic PE–PUFA–OOH, which leads to ferroptosis. Antioxidants work in the same way during termination.