When Pathways Converge: Iron, Lipid Peroxidation, and α-Synuclein in Ferroptosis-Driven Dopaminergic Neurodegeneration.
When Pathways Converge: Iron, Lipid Peroxidation, and α-Synuclein in Ferroptosis-Driven Dopaminergic Neurodegeneration.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Catarina, BR · Author affiliation
Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil.Location evidence
Florianópolis, BR · Author affiliation
Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil.Location evidence
New York City, US · Author affiliation
Department of Biological Sciences, Columbia University, New York, New York, USA.Location evidence
Irving, US · Author affiliation
Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Digestive and Liver Disease Research Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA.Location evidence
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Original abstract
The selective degeneration of dopaminergic neurons is a hallmark of Parkinson's disease and related disorders. While multiple cell death pathways have been implicated, ferroptosis has recently emerged as a critical mechanism. This iron-dependent form of regulated cell death is driven by the accumulation of phospholipid hydroperoxides, leading to oxidative membrane damage. Dopaminergic neurons are intrinsically vulnerable to ferroptosis due to their high iron content, active dopamine metabolism (a source of reactive oxygen species), and relatively low antioxidant defenses. Here we synthesize evidence linking ferroptosis to dopaminergic neurodegeneration in Parkinson's disease and related conditions, detailing the molecular mechanisms involving iron dyshomeostasis, lipid peroxidation, and α-synuclein pathology. We further evaluate growing preclinical data demonstrating that pharmacological inhibition of ferroptosis is neuroprotective and discuss the clinical implications, therapeutic potential, and ongoing challenges of translating these findings into effective treatments for patients.