Ferroptosis as a Major Factor and Therapeutic Target for Neuroinflammation in Parkinson’s Disease

Abstract

Mounting evidence suggests that ferroptosis is not just a consequence but also a fundamental contributor to the development and progression of Parkinson’s disease (PD). Ferroptosis is characterized as iron-dependent regulated cell death caused by excessive lipid peroxidation, leading to plasma membrane rupture, release of damage-associated molecular patterns, and neuroinflammation. Due to the crucial role of intracellular iron in mediating the production of reactive oxygen species and the formation of lipid peroxides, ferroptosis is intimately controlled by regulators involved in many aspects of iron metabolism, including iron uptake, storage and export, and by pathways constituting the antioxidant systems. Translational and transcriptional regulation of iron homeostasis and redox status provide an integrated network to determine the sensitivity of ferroptosis. We herein review recent advances related to ferroptosis, ranging from fundamental mechanistic discoveries and cutting-edge preclinical animal studies, to clinical trials in PD and the regulation of neuroinflammation via ferroptosis pathways. Elucidating the roles of ferroptosis in the survival of dopaminergic neurons and microglial activity can enhance our understanding of the pathogenesis of PD and provide opportunities for the development of novel prevention and treatment strategies.

Selenium Alleviates Cerebral Ischemia/Reperfusion Injury by Regulating Oxidative Stress, Mitochondrial Fusion and Ferroptosis

“…A characteristic of cell ferroptosis is the accumulation of lipid reactive oxygen species, leading to oxidative stress and cell death, which has been shown to have significant implications in diverse brain diseases [ 30 , 31 ], such as Alzheimer’s disease [ 32 ], Parkinson’s disease [ 33 ], and cerebral ischemic disease [ 34 ]. Ferroptosis process is closely related to oxidative stress, and usually accompanied by the increase of iron content.…”

Growth Differentiation Factor 15 Regulates Oxidative Stress-Dependent Ferroptosis Post Spinal Cord Injury by Stabilizing the p62-Keap1-Nrf2 Signaling Pathway

“…We found that silencing GDF15 impeded axonal regeneration and remyelination and aggravated nervous tissue loss post SCI. Previous studies have shown that overloaded iron-induced ferroptosis promoted the activation of microglia by a ROS-independent mechanism and the latter caused the secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), which triggered neuroinflammation ( Ko et al, 2021 ). In our study, we observed that after deteriorative ferroptosis caused by the knockdown of GDF15, neuroinflammation post SCI was also more severe, which suggested that GDF15 was associated with ferroptosis-mediated neuroinflammation.…”

The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities

“…Disease [85,86]. Ferroptosis is seen as a novel therapeutic for several neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's disease [87,88].…”