Ferroptosis Mechanisms Involved in Neurodegenerative Diseases

Abstract

Ferroptosis is a type of cell death that was described less than a decade ago. It is caused by the excess of free intracellular iron that leads to lipid (hydro) peroxidation. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. Since the 1960s, increased concentration of iron in the central nervous system has been associated with oxidative stress, oxidation of proteins and lipids, and cell death. Here, we review the main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism. Moreover, the association of ferroptosis with the pathophysiology of some neurodegenerative diseases, namely Alzheimer’s, Parkinson’s, and Huntington’s diseases, has also been addressed.

Global Research Trends of Ferroptosis: A Rapidly Evolving Field With Enormous Potential

“…Once the basic knowledge such as molecular mechanism and regulation of ferroptosis is recognized, a spectrum of potential clinical applications, including drug discovery and development, will follow. For application studies, ferroptosis pathways have gained attention as novel therapeutic targets for treatment of many diseases, in particular for cancers and neurodegenerative diseases ( Chen et al, 2015 ; Liang et al, 2019 ; Lelièvre et al, 2020 ; Reichert et al, 2020 ; Sun et al, 2020 ). Therefore, parallel to the mechanism studies of ferroptosis, further studies should focus on clinical application and transformation research.…”

“…Growing evidence implicates ferroptosis participating in neurodegenerative diseases including Alzheimer disease (AD), Parkinson disease (PD), and Huntington disease (HD). AD is considered a common aging-related neurodegenerative disorder characterized by inflammation of the nerve cells, oxidative damage, and the formation of β-amyloid plaques ( Reichert et al, 2020 ). Previous studies have demonstrated the iron accumulation in the cerebral cortex was associated with the development of AD.…”

“…Over the past few years, the cumulative evidence indicated that impaired ferroptosis is implicated in the development of various pathological conditions, most notably cancer ( Zielke et al, 2018 ; Yang et al, 2019 , 2020 ), neurodegenerative diseases ( Reichert et al, 2020 ; Sun et al, 2020 ), tissue ischemia/reperfusion injury ( Tuo et al, 2017 ; Li et al, 2019 ), craniocerebral trauma ( Tang et al, 2020 ), and inflammation ( Proneth and Conrad, 2019 ). Therefore, it is a promising field to develop potent ferroptosis inducers or inhibitors with high potential for preventing and treating the aforementioned diseases, as well as several other underlying disorders related to ferroptosis.…”

Is Chelation Therapy a Potential Treatment for Parkinson’s Disease?

“…Ferroptosis is a form of regulated cell death involving the iron-dependent formation of reactive free radicals, resulting in the generation of lipid hydroperoxides within membrane phospholipids rich in polyunsaturated fatty acids (PUFAs). Three factors are involved in ferroptotic cell death: increased free intracellular iron, oxidation of membrane PUFAs, and depletion of the glutathione/glutathione peroxidase system responsible for the reduction of lipid peroxides to lipid alcohols [ 78 ]. Recent studies involving both patients and animal models have suggested that ferroptosis is likely to be involved in a number of neurodegenerative diseases, including PD.…”

Paraoxonase Role in Human Neurodegenerative Diseases

“…The etiology of the several neurodegenerative diseases is still unclear, being multifactorial [ 3 , 4 ]. First, there are different neurodegenerative diseases, since the CNS is composed of different cell populations, in different areas, with highly specialized and unique functions.…”