帕金森病(Parkinson's disease，PD)是一种以肌强直、静止性震颤及姿势障碍为主要症状的神经退行性疾病。研究表明，铁负荷增加、氧化应激和脂质过氧化在PD的发病机制中起关键作用，而铁死亡作为一种铁依赖性、脂质过氧化驱动的细胞死亡模式，可能是治疗PD的重要突破口。运动作为一种非药物干预手段，能够通过调控铁代谢相关蛋白(如铁调素、铁蛋白、铁转运蛋白)、增强抗氧化防御系统(如谷胱甘肽、谷胱甘肽过氧化物酶4、超氧化物歧化酶)、减少α突触核蛋白(α-synuclein)聚集及调节谷氨酸水平，从而抑制铁死亡的发生，保护神经元，预防和延缓PD的进展。具体而言，运动干预可通过下调二价金属离子转运体1(divalent metal transporter 1，DMT1)和上调膜铁转运蛋白1(ferroportin 1，FPN1)表达，减少细胞内铁积聚，通过增强抗氧化酶活性，降低脂质过氧化水平，通过减少α-synuclein的异常聚集，减轻其引发的氧化应激损伤，通过调节谷氨酸代谢，减轻兴奋性毒性。本文综述了铁死亡在PD中的作用机制及其与运动干预的关系，旨在为PD的预防和治疗提供新的思路和策略。
Exercise-induced Modulation of Ferroptosis:Potential Mechanisms for Improvement in Parkinson's Disease
Parkinson's disease(PD)is a neurodegenerative disorder characterized by muscle rigidity,resting tremor,and postural instability,which severely impair the quality of life in middle-aged and elderly individuals.PD's pathogenesis is complex,involving oxidative stress,immune inflammation,and genetic factors.Despite extensive research,precise therapeutic targets for PD remain elusive,necessitating further investigation into its underlying mechanisms.Recent studies highlight the pivotal role of regional brain iron overload,oxidative stress,and lipid peroxidation in PD's pathogenesis.Ferroptosis,a form of regulated cell death driven by iron dependency and lipid peroxidation,has emerged as a critical factor in PD pathology.This review examines the relationship between ferroptosis and PD and explores the potential of exercise as a therapeutic intervention to modulate ferroptosis and alleviate PD symptoms.Ferroptosis,distinct from other forms of cell death such as necrosis,autophagy,pyroptosis,and apoptosis,is characterized by mitochondrial shrinkage,reduced cristae,and membrane collapse,without nuclear fragmentation,DNA cleavage,or caspase activation.It is induced by the accumulation of intracellular Fe2+,which enhances lipid peroxidation and reactive oxygen species(ROS)generation,ultimately leading to cell death.Studies show disrupted iron metabolism in PD patients,with elevated iron levels in dopaminergic neurons of the substantia nigra correlating with disease severity.Iron chelation therapy has shown promise in alleviating PD symptoms by reducing brain iron levels,highlighting the significance of iron metabolism in PD pathogenesis.Lipid peroxidation,a hallmark of ferroptosis,involves the oxidation of polyunsaturated fatty acids(PUFAs)in cell membranes,compromising membrane integrity and increasing permeability.Elevated lipid peroxidation in the substantia nigra contributes to neuronal damage in PD.Enzymes such as ACSL4 and LPCAT3,crucial in PUFA metabolism,play significant roles in ferroptosis.Exercise has been shown to modulate these enzymes,potentially reducing lipid peroxidation and preventing ferroptosis in PD.Glutathione(GSH)metabolism is another crucial factor in ferroptosis regulation.GSH depletion impairs ROS detoxification,exacerbating oxidative stress and lipid peroxidation.PD patients exhibit reduced GSH levels in the substantia nigra,making dopaminergic neurons more vulnerable to oxidative damage.Exercise enhances GSH synthesis and activity,mitigating oxidative stress and ferroptosis in PD.α-Synuclein aggregation,a hallmark of PD,is closely linked to iron metabolism and oxidative stress.Excessive α-synuclein binds to iron,promoting its aggregation and inducing ferroptosis.Exercise has been found to reduceα-synuclein accumulation and its pathological phosphorylation,potentially through the upregulation of neuroprotective proteins like DJ-1 and Irisin.These proteins enhance antioxidant defenses and facilitate α-synuclein degradation,providing a protective effect against PD progression.Additionally,glutamate excitotoxicity,driven by dysregulated glutamate metabolism and receptor activity,contributes to ferroptosis in PD.Exercise modulates glutamate levels and receptor expression,reducing excitotoxicity and iron-induced neuronal damage.In conclusion,emerging research suggests that exercise may inhibit ferroptosis through multiple mechanisms,including regulation of iron metabolism,enhancement of antioxidant defenses,reduction of α-synuclein aggregation,and modulation of glutamate metabolism.These findings highlight the potential of exercise as a non-pharmacological intervention in the prevention and treatment of PD.Further research is needed to elucidate precise mechanisms and optimize exercise protocols for maximum therapeutic benefit.
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