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.
Highlights
We aimed to review the latest research on ferroptosis to further the understanding of its pathogenesis and to propose potential targets for the treatment of Parkinson’s disease (PD)
The main iron-regulating mRNAs can be regulated by aconitase 1 (ACO1)/iron-responsive element binding protein 2 (IREB2), including the genes involved in iron import (e.g., transferrin receptor (TFRC) and SLC11A2), storage (e.g., ferritin heavy chain 1 (FTH1) and ferritin light chain (FTL)), and export (e.g., SLC40A1)
Advanced investigations have provided further insight into our understanding of ferroptosis, which involves the integration of highly organized systems that regulate iron metabolism, lipid peroxidation, and antioxidant defense
Summary
The global death due to PD increased by approximately 40%. A reduction in the number of dopaminergic neurons and an abnormal accumulation of α-synuclein (α-syn) result in a shortage of dopamine from the substantia nigra–striatum pathway, causing clinical symptoms such as tremor, bradykinesia, rigidity, and postural balance disorders [2,3]. In multicellular organisms, regulated cell death (RCD) is a function necessary for Apoptotic bodiesdevelopment and maintenance of tissue homoeostasis, as well as to elimithe normal. In addition to apoptosis and Chromatin condensation necroptosis, Shrinkage of cell studies have recently revealed new types of RCD, including pyroptosis and ferroptosis [8,9,10,11]. 4; HO-1, hemehave oxygenase-1; immunogenic cell death; Nec1), and signaling pathway (Figure 1) cell features.
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