82
Views
0
CrossRef citations to date
0
Altmetric
REVIEW

Mapping the Research of Ferroptosis in Parkinson’s Disease from 2013 to 2023: A Scientometric Review

ORCID Icon, , , , ORCID Icon, , & show all
Pages 1053-1081 | Received 04 Jan 2024, Accepted 05 Mar 2024, Published online: 03 Apr 2024

References

  • He T, Lin X, Su A, et al. Mitochondrial dysfunction-targeting therapeutics of natural products in Parkinson’s disease. Front Pharmacol. 2023;14:1117337.
  • Collaborators GBDPs D. Global, regional, and national burden of Parkinson’s disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17(11):939–953.
  • Dorsey ER, Sherer T, Okun MS, Bloem BR. The Emerging Evidence of the Parkinson Pandemic. J Parkinsons Dis. 2018;8(s1):S3–S8.
  • Tolosa E, Garrido A, Scholz SW, Poewe W. Challenges in the diagnosis of Parkinson’s disease. Lancet Neurol. 2021;20(5):385–397.
  • Chen YC, Liaw YC, Nfor ON, et al. Epigenetic regulation of Parkinson’s disease risk variant GPNMB cg17274742 methylation by sex and exercise from Taiwan Biobank. Front Aging Neurosci. 2023;15:1235840.
  • Geng Y, Long X, Zhang Y, et al. FTO-targeted siRNA delivery by MSC-derived exosomes synergistically alleviates dopaminergic neuronal death in Parkinson’s disease via m6A-dependent regulation of ATM mRNA. J Transl Med. 2023;21(1):652.
  • Moujalled D, Strasser A, Liddell JR. Molecular mechanisms of cell death in neurological diseases. Cell Death Differ. 2021;28(7):2029–2044.
  • Dexter DT, Wells FR, Agid F, et al. Increased nigral iron content in postmortem parkinsonian brain. Lancet. 1987;2(8569):1219–1220.
  • Dexter D, Carter C, Agid F, et al. Lipid peroxidation as cause of nigral cell death in Parkinson’s disease. Lancet. 1986;2(8507):639–640.
  • Sian J, Dexter DT, Lees AJ, et al. Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol. 1994;36(3):348–355.
  • Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299(5604):256–259.
  • Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575(7784):688–692.
  • Mahoney-Sanchez L, Bouchaoui H, Ayton S, Devos D, Duce JA, Devedjian JC. Ferroptosis and its potential role in the physiopathology of Parkinson’s Disease. Prog Neurobiol. 2021;196.
  • Wang ZL, Yuan L, Li W, Li JY. Ferroptosis in Parkinson’s disease: glia-neuron crosstalk. Trends Mol Med. 2022;28(4):258–269.
  • Chen C, Song M. Visualizing a field of research: a methodology of systematic scientometric reviews. PLoS One. 2019;14(10):e0223994.
  • Si W, Huang Z, Li X, et al. Super-enhancer-driven Sorting Nexin 5 expression promotes dopaminergic neuronal ferroptosis in Parkinson’s disease models. Biochem Biophys Res Commun. 2021;567:35–41.
  • Huang Z, Han J, Wu P, et al. Sorting Nexin 5 Plays an Important Role in Promoting Ferroptosis in Parkinson’s Disease. Oxid Med Cell Longev. 2022;2022:5463134.
  • Bouchaoui H, Mahoney-Sanchez L, Garçon G, et al. ACSL4 and the lipoxygenases 15/15B are pivotal for ferroptosis induced by iron and PUFA dyshomeostasis in dopaminergic neurons. Free Radic Biol Med. 2023;195(8):145–157.
  • Mahoney-Sanchez L, Bouchaoui H, Boussaad I, et al. Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modulation of ether-phospholipid membrane composition. Cell Rep. 2022;40(8):111231.
  • Jiang L, Chen XB, Wu Q, et al. The C terminus of DJ-1 determines its homodimerization, MGO detoxification activity and suppression of ferroptosis. Acta Pharmacol Sin. 2021;42(7):1150–1159.
  • Zeng X, An H, Yu F, et al. Benefits of Iron Chelators in the Treatment of Parkinson’s Disease. Neurochem Res. 2021;46(5):1239–1251.
  • Lin F, Chen Y, Mo W, et al. A bibliometric analysis of autophagy in lung diseases from 2012 to 2021. Front Immunol. 2022;13:1092575.
  • Do Van B, Gouel F, Jonneaux A, et al. Ferroptosis, a newly characterized form of cell death in Parkinson’s disease that is regulated by PKC. Neurobiol Dis. 2016;94:169–178.
  • Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an Iron-Dependent Form of Nonapoptotic Cell Death. Cell. 2012;149(5):1060–1072.
  • Angeli JPF, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16(12):567.
  • Devos D, Moreau C, Devedjian JC, et al. Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal. 2014;21(2):195–210.
  • Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci U S A. 2016;113(34):E4966–75.
  • Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of Ferroptotic Cancer Cell Death by GPX4. Cell. 2014;156(1–2).
  • Skouta R, Dixon SJ, Wang JL, et al. Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models. J Am Chem Soc. 2014;136(12):4551–4556.
  • Gao MH, Monian P, Quadri N, Ramasamy R, Jiang XJ. Glutaminolysis and Transferrin Regulate Ferroptosis. Molecular Cell. 2015;59(2):298–308.
  • Ayton S, Lei P, Hare DJ, et al. Parkinson’s Disease Iron Deposition Caused by Nitric Oxide-Induced Loss of β-Amyloid Precursor Protein. J Neurosci. 2015;35(8):3591–3597.
  • Jiang L, Kon N, Li TY, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520(7545):57–62.
  • Dixon SJ, Winter GE, Musavi LS, et al. Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death. ACS Chem Biol. 2015;10(7):1604–1609.
  • Hambright WS, Fonseca RS, Chen LJ, Na R, Ran QT. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 2017;12:8–17. doi:10.1016/j.redox.2017.01.021
  • Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nature Chem Biol. 2014;10(1):9–17. doi:10.1038/nchembio.1416
  • Xie Y, Hou W, Song X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23(3):369–379.
  • Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63(1):173–184.
  • Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017;171(2):273–285.
  • Guiney SJ, Adlard PA, Bush AI, Finkelstein DI, Ayton S. Ferroptosis and cell death mechanisms in Parkinson’s disease. Neurochem Int. 2017;104:34–48.
  • Angelova PR, Choi ML, Berezhnov AV, et al. Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation. Cell Death Differ. 2020;27(10):2781–2796.
  • Masaldan S, Bush AI, Devos D, Rolland AS, Moreau C. Striking while the iron is hot: iron metabolism and ferroptosis in neurodegeneration. Free Radic Biol Med. 2019;133:221–233.
  • Zhang P, Chen L, Zhao Q, et al. Ferroptosis was more initial in cell death caused by iron overload and its underlying mechanism in Parkinson’s disease. Free Radic Biol Med. 2020;152:227–234.
  • Weiland A, Wang YM, Wu WH, et al. Ferroptosis and Its Role in Diverse Brain Diseases. Mol Neurobiol. 2019;56(7):4880–4893.
  • Tian Y, Lu J, Hao XQ, et al. FTH1 Inhibits Ferroptosis Through Ferritinophagy in the 6-OHDA Model of Parkinson’s Disease. Neurotherapeutics. 2020;17(4):1796–1812.
  • Abdalkader M, Lampinen R, Kanninen KM, Malm TM, Liddell JR. Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration. Front Neurosci. 2018;12:466.
  • Sun YR, He LB, Wang TY, et al. Activation of p62-Keap1-Nrf2 Pathway Protects 6-Hydroxydopamine-Induced Ferroptosis in Dopaminergic Cells. Mol Neurobiol. 2020;57(11):4628–4641.3.
  • Southon A, Szostak K, Acevedo KM, et al. CuII (atsm) inhibits ferroptosis: implications for treatment of neurodegenerative disease. Br J Pharmacol. 2020;177(3):656–667.
  • Ito K, Eguchi Y, Imagawa Y, Akai S, Mochizuki H, Tsujimoto Y. MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells. Cell Death Discov. 2017;3:17013.
  • Liddell JR, White AR. Nexus between mitochondrial function, iron, copper and glutathione in Parkinson’s disease. Neurochem Int. 2018;117:126–138.
  • Devos D, Cabantchik ZI, Moreau C, et al. Conservative iron chelation for neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis. J Neural Transm. 2020;127(2):189–203.
  • Chen LJ, Hambright WS, Na R, Ran QT. Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis. J Biol Chem. 2015;290(47):28097–28106.
  • Ayton S, Lei P. Nigral Iron Elevation Is an Invariable Feature of Parkinson’s Disease and Is a Sufficient Cause of Neurodegeneration. Biomed Res Int. 2014;2014:581256.
  • Li Q, Han XN, Lan X, et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain. Jci Insight. 2017;2(7):e90777.
  • Hare DJ, Double KL. Iron and dopamine: a toxic couple. Brain. 2016;139(4):1026–1035.
  • Shimada K, Skouta R, Kaplan A, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016;12(7):497–503.
  • Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13(1):91–98.
  • Kagan VE, Mao G, Qu F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13(1):81–90.
  • Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693–698.
  • Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008;15(3):234–245.
  • Ward R, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014;13(10):1045–1060.
  • Yang WS, Stockwell BR. Ferrootosis: death by Lipid Peroxidation. Trends Cell Biol. 2016;26(3):165–176.
  • Martin-Bastida A, Ward RJ, Newbould R, et al. Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Sci Rep. 2017;7(1):1398.
  • Yagoda N, Von Rechenberg M, Zaganjor E, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447(7146):864–868.
  • Yuan H, Li XM, Zhang XY, Kang R, Tang DL. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016;478(3):1338–1343.
  • Qiu Y, Cao Y, Cao W, Jia Y, Lu N. The Application of Ferroptosis in Diseases. Pharmacol Res. 2020;159:104919.
  • Angelova PR, Esteras N, Abramov AY. Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: finding ways for prevention. Med Res Rev. 2021;41(2):770–784.
  • Thapa K, Khan H, Kanojia N, Singh TG, Kaur A, Kaur G. Therapeutic Insights on Ferroptosis in Parkinson’s disease. Eur J Pharmacol. 2022;930:175133.
  • Han X, Zhang J, Chen S, Yu W, Zhou Y, Gu X. Mapping the current trends and hotspots of vascular cognitive impairment from 2000-2021: a bibliometric analysis. CNS Neurosci Ther. 2023;29(3):771–782.
  • Li Y, Zheng JJ, Wu X, Gao W, Liu CJ. Postural control of Parkinson’s disease: a visualized analysis based on Citespace knowledge graph. Front Aging Neurosci. 2023;15:1136177.
  • Zhong D, Luo S, Zheng L, Zhang Y, Jin R. Epilepsy Occurrence and Circadian Rhythm: a Bibliometrics Study and Visualization Analysis via CiteSpace. Front Neurol. 2020;11:984.
  • Villalon-Garcia I, Povea-Cabello S, Alvarez-Cordoba M, et al. Vicious cycle of lipid peroxidation and iron accumulation in neurodegeneration. Neural Regen Res. 2023;18(6):1196–1202.
  • Villalon-Garcia I, Alvarez-Cordoba M, Povea-Cabello S, et al. Vitamin E prevents lipid peroxidation and iron accumulation in PLA2G6-Associated Neurodegeneration. Neurobiol Dis. 2022;165:105649.
  • Hohn A, Jung T, Grimm S, Grune T. Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radic Biol Med. 2010;48(8):1100–1108.
  • Zeidan RS, Han SM, Leeuwenburgh C, Xiao R. Iron homeostasis and organismal aging. Ageing Res Rev. 2021;72:101510.
  • Brunk UT, Terman A. Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic Biol Med. 2002;33(5):611–619.
  • Moore MN, Sforzini S, Viarengo A, et al. Antagonistic cytoprotective effects of C(60) fullerene nanoparticles in simultaneous exposure to benzo[a]pyrene in a molluscan animal model. Sci Total Environ. 2021;755(Pt 1):142355.
  • Tian Y, Tian Y, Yuan Z, et al. Iron Metabolism in Aging and Age-Related Diseases. Int J Mol Sci. 2022;23(7):3612.
  • Tian R, Abarientos A, Hong J, et al. Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis. Nat Neurosci. 2021;24(7):1020–1034.
  • Shi L, Huang C, Luo Q, et al. The Association of Iron and the Pathologies of Parkinson’s Diseases in MPTP/MPP(+)-Induced Neuronal Degeneration in Non-human Primates and in Cell Culture. Front Aging Neurosci. 2019;11:215.
  • Belaidi AA, Bush AI. Iron neurochemistry in Alzheimer’s disease and Parkinson’s disease: targets for therapeutics. J Neurochem. 2016;139(Suppl 1):179–197.
  • Thomas GEC, Leyland LA, Schrag AE, Lees AJ, Acosta-Cabronero J, Weil RS. Brain iron deposition is linked with cognitive severity in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2020;91(4):418–425.
  • Pesch B, Casjens S, Woitalla D, et al. Impairment of Motor Function Correlates with Neurometabolite and Brain Iron Alterations in Parkinson’s Disease. Cells. 2019;8(2):96.
  • Dexter DT, Wells FR, Lees AJ, et al. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem. 1989;52(6):1830–1836.
  • Cho SJ, Bae YJ, Kim JM, et al. Iron-sensitive magnetic resonance imaging in Parkinson’s disease: a systematic review and meta-analysis. J Neurol. 2021;268(12):4721–4736.
  • Good PF, Olanow CW, Perl DP. Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson’s disease: a LAMMA study. Brain Res. 1992;593(2):343–346.
  • Wang Z, Luo XG, Gao C. Utility of susceptibility-weighted imaging in Parkinson’s disease and atypical Parkinsonian disorders. Transl Neurodegener. 2016;5:17.
  • Wang JY, Zhuang QQ, Zhu LB, et al. Meta-analysis of brain iron levels of Parkinson’s disease patients determined by postmortem and MRI measurements. Sci Rep. 2016;6:36669.
  • Ji S, Zhang S, Mao Z, et al. Quantitative assessment of iron deposition in Parkinson’s disease using enhanced T2 star-weighted angiography. Neurol India. 2016;64(3):428–435.
  • Biondetti E, Santin MD, Valabrègue R, et al. The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson’s disease. Brain. 2021;144(10):3114–3125.
  • Song N, Wang J, Jiang H, Xie J. Ferroportin 1 but not hephaestin contributes to iron accumulation in a cell model of Parkinson’s disease. Free Radic Biol Med. 2010;48(2):332–341.
  • Jiang H, Song N, Xu H, Zhang S, Wang J, Xie J. Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell Res. 2010;20(3):345–356.
  • Zhao X, Shao Z, Zhang Y, Liu F, Liu Z, Liu Z. Ceruloplasmin in Parkinson’s disease and the nonmotor symptoms. Brain Behav. 2018;8(6):e00995.
  • Barbariga M, Curnis F, Andolfo A, et al. Ceruloplasmin functional changes in Parkinson’s disease-cerebrospinal fluid. Mol Neurodegener. 2015;10:59.
  • Lei P, Ayton S, Finkelstein DI, et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med. 2012;18(2):291–295.
  • Kaur D, Yantiri F, Rajagopalan S, et al. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron. 2003;37(6):899–909.
  • Blackinton J, Kumaran R, van der Brug MP, et al. Post-transcriptional regulation of mRNA associated with DJ-1 in sporadic Parkinson disease. Neurosci Lett. 2009;452(1):8–11.
  • Bellinger FP, Bellinger MT, Seale LA, et al. Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson’s brain. Mol Neurodegener. 2011;6(1):8.
  • Vallerga CL, Zhang F, Fowdar J, et al. Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson’s disease. Nat Commun. 2020;11(1):1238.
  • Liu Y, Ma X, Fujioka H, Liu J, Chen S, Zhu X. DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1. Proc Natl Acad Sci U S A. 2019;116(50):25322–25328.
  • Cao J, Chen X, Jiang L, et al. DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase. Nat Commun. 2020;11(1):1251.
  • Guo Q, Wang B, Wang X, Smith WW, Zhu Y, Liu Z. Activation of Nrf2 in Astrocytes Suppressed PD-Like Phenotypes via Antioxidant and Autophagy Pathways in Rat and Drosophila Models. Cells. 2021;10(8):1850.
  • Xiao H, Lv F, Xu W, Zhang L, Jing P, Cao X. Deprenyl prevents MPP(+)-induced oxidative damage in PC12 cells by the upregulation of Nrf2-mediated NQO1 expression through the activation of PI3K/Akt and Erk. Toxicology. 2011;290(2–3):286–294.
  • Anandhan A, Chen W, Nguyen N, Madhavan L, Dodson M, Zhang DD. α-Syn overexpression, NRF2 suppression, and enhanced ferroptosis create a vicious cycle of neuronal loss in Parkinson’s disease. Free Radic Biol Med. 2022;192:130–140.
  • Zeitler L, Fiore A, Meyer C, et al. Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism. Elife. 2021;10:e64806.
  • Costa I, Barbosa DJ, Benfeito S, et al. Molecular mechanisms of ferroptosis and their involvement in brain diseases. Pharmacol Ther. 2023;108373.
  • Cleren C, Yang L, Lorenzo B, et al. Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of Parkinsonism. J Neurochem. 2008;104(6):1613–1621.
  • Mischley LK, Allen J, Bradley R. Coenzyme Q10 deficiency in patients with Parkinson’s disease. J Neurol Sci. 2012;318(1–2):567.
  • Dexter DT, Carter CJ, Wells FR, et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem. 1989;52(2):381–389.
  • Sharon R, Bar-Joseph I, Mirick GE, Serhan CN, Selkoe DJ. Altered fatty acid composition of dopaminergic neurons expressing alpha-synuclein and human brains with alpha-synucleinopathies. J Biol Chem. 2003;278(50):49874–49881.
  • Fedorova TN, Logvinenko AA, Poleshchuk VV. Lipid Peroxidation Products in the Blood Plasma of Patients with Parkinson’s Disease as Possible Biomarkers of Different Stages of the Disease. Neurochemical J. 2019;13(4):391–395.
  • Tang F, Zhou LY, Li P, et al. Inhibition of ACSL4 Alleviates Parkinsonism Phenotypes by Reduction of Lipid Reactive Oxygen Species. Neurotherapeutics. 2023;20(4):1154–1166.
  • Yue M, Wei J, Chen W, Hong D, Chen T, Fang X. Neurotrophic Role of the Next-Generation Probiotic Strain L. lactis MG1363-pMG36e-GLP-1 on Parkinson’s Disease via Inhibiting Ferroptosis. Nutrients. 2022;14(22):4886.
  • Yu X, Yang Y, Zhang B, et al. Ketone Body β-Hydroxybutyric Acid Ameliorates Dopaminergic Neuron Injury Through Modulating Zinc Finger Protein 36/Acyl-CoA Synthetase Long-Chain Family Member Four Signaling Axis-Mediated Ferroptosis. Neuroscience. 2023;509:157–172.
  • Chen D, Chu B, Yang X, et al. iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nat Commun. 2021;12(1):3644.
  • Beharier O, Tyurin VA, Goff JP, et al. PLA2G6 guards placental trophoblasts against ferroptotic injury. Proc Natl Acad Sci U S A. 2020;117(44):27319–27328.
  • Sun WY, Tyurin VA, Mikulska-Ruminska K, et al. Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal. Nat Chem Biol. 2021;17(4):465–476. doi:10.1038/s41589-020-00734-x
  • Guo JJ, Yue F, Song DY, et al. Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis. Cell Death Dis. 2021;12(1):81.
  • Minakaki G, Krainc D, Burbulla LF. The Convergence of Alpha-Synuclein, Mitochondrial, and Lysosomal Pathways in Vulnerability of Midbrain Dopaminergic Neurons in Parkinson’s Disease. Front Cell Dev Biol. 2020;8:580634.
  • Xiao Y, Chen X, Huang S, et al. Iron promotes α-synuclein aggregation and transmission by inhibiting TFEB-mediated autophagosome-lysosome fusion. J Neurochem. 2018;145(1):34–50.
  • el-Agnaf OM, Irvine GB. Aggregation and neurotoxicity of alpha-synuclein and related peptides. Biochem Soc Trans. 2002;30(4):559–565.
  • Uversky VN, Li J, Fink AL. Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson’s disease and heavy metal exposure. J Biol Chem. 2001;276(47):44284–44296.
  • Peng Y, Wang C, Xu HH, Liu YN, Zhou F. Binding of alpha-synuclein with Fe(III) and with Fe(II) and biological implications of the resultant complexes. J Inorg Biochem. 2010;104(4):365–370.
  • Golts N, Snyder H, Frasier M, Theisler C, Choi P, Wolozin B. Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein. J Biol Chem. 2002;277(18):16116–16123.
  • Friedlich AL, Tanzi RE, Rogers JT. The 5’-untranslated region of Parkinson’s disease alpha-synuclein messenger RNA contains a predicted iron responsive element. Mol Psychiatry. 2007;12(3):222–223.
  • Febbraro F, Giorgi M, Caldarola S, Loreni F, Romero-Ramos M. α-Synuclein expression is modulated at the translational level by iron. Neuroreport. 2012;23(9):576–580.
  • Cahill CM, Lahiri DK, Huang X, Rogers JT. Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases. Biochim Biophys Acta. 2009;1790(7):615–628.
  • Davies P, Moualla D, Brown DR. Alpha-synuclein is a cellular ferrireductase. PLoS One. 2011;6(1):e15814.
  • Alam P, Bousset L, Melki R, Otzen DE. α-synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities. J Neurochemistry. 2019;150(5):522–534.
  • Binolfi A, Rasia RM, Bertoncini CW, et al. Interaction of alpha-synuclein with divalent metal ions reveals key differences: a link between structure, binding specificity and fibrillation enhancement. J Am Chem Soc. 2006;128(30):9893–9901. doi:10.1021/ja0618649
  • Longhena F, Faustini G, Bellucci A. Study of alpha-synuclein fibrillation: state of the art and expectations. Neural Regen Res. 2020;15(1):59–60.
  • Lin KJ, Chen SD, Lin KL, et al. Iron Brain Menace: the Involvement of Ferroptosis in Parkinson Disease. Cells. 2022;11(23):3829.
  • Baksi S, Tripathi AK, Singh N. Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: implications for visual manifestations of Parkinson’s disease. Free Radic Biol Med. 2016;97:292–306.
  • Bi M, Du X, Jiao Q, Liu Z, Jiang H. α-Synuclein Regulates Iron Homeostasis via Preventing Parkin-Mediated DMT1 Ubiquitylation in Parkinson’s Disease Models. ACS Chem Neurosci. 2020;11(11):1682–1691.
  • Zhu ZJ, Wu KC, Yung WH, Qian ZM, Ke Y. Differential interaction between iron and mutant alpha-synuclein causes distinctive Parkinsonian phenotypes in Drosophila. Biochim Biophys Acta. 2016;1862(4):518–525.
  • Jia F, Song N, Wang W, Du X, Chi Y, Jiang H. High Dietary Iron Supplement Induces the Nigrostriatal Dopaminergic Neurons Lesion in Transgenic Mice Expressing Mutant A53T Human Alpha-Synuclein. Front Aging Neurosci. 2018;10:97.
  • Febbraro F, Andersen KJ, Sanchez-Guajardo V, Tentillier N, Romero-Ramos M. Chronic intranasal deferoxamine ameliorates motor defects and pathology in the α-synuclein rAAV Parkinson’s model. Exp Neurol. 2013;247:45–58.
  • Carboni E, Tatenhorst L, Tönges L, et al. Deferiprone Rescues Behavioral Deficits Induced by Mild Iron Exposure in a Mouse Model of Alpha-Synuclein Aggregation. Neuromolecular Med. 2017;19(2–3).
  • Golovko MY, Rosenberger TA, Faergeman NJ, et al. Acyl-CoA synthetase activity links wild-type but not mutant alpha-synuclein to brain arachidonate metabolism. Biochemistry. 2006;45(22):6956–6966.
  • Ouberai MM, Wang J, Swann MJ, et al. α-Synuclein senses lipid packing defects and induces lateral expansion of lipids leading to membrane remodeling. J Biol Chem. 2013;288(29):20883–20895.
  • Shahmoradian SH, Lewis AJ, Genoud C, et al. Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nat Neurosci. 2019;22(7):1099–1109.
  • Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology. 1985;35(7):949–956.
  • Lin KJ, Wang TJ, Chen SD, et al. Two Birds One Stone: the Neuroprotective Effect of Antidiabetic Agents on Parkinson Disease-Focus on Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors. Antioxidants (Basel). 2021;10(12):1935.
  • Nguyen M, Wong YC, Ysselstein D, Severino A, Krainc D. Synaptic, Mitochondrial, and Lysosomal Dysfunction in Parkinson’s Disease. Trends Neurosci. 2019;42(2):140–149.
  • Lesage S, Drouet V, Majounie E, et al. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. Am J Hum Genet. 2016;98(3):500–513.
  • Gregory A, Westaway SK, Holm IE, et al. Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology. 2008;71(18):1402–1409.
  • Kinghorn KJ, Castillo-Quan JI, Bartolome F, et al. Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. Brain. 2015;138(7):1801–1816.
  • Smolders S, Van Broeckhoven C. Genetic perspective on the synergistic connection between vesicular transport, lysosomal and mitochondrial pathways associated with Parkinson’s disease pathogenesis. Acta Neuropathol Commun. 2020;8(1):63.
  • Billingsley KJ, Barbosa IA, Bandrés-Ciga S, et al. Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset. NPJ Parkinsons Dis. 2019;5:8.
  • Wang Y, Liu N, Lu B. Mechanisms and roles of mitophagy in neurodegenerative diseases. CNS Neurosci Ther. 2019;25(7):859–875. doi:10.1111/cns.13140
  • Daher B, Vučetić M, Pouysségur J. Cysteine Depletion, a Key Action to Challenge Cancer Cells to Ferroptotic Cell Death. Front Oncol. 2020;10:723.
  • Chen X, Kang R, Kroemer G, Tang D. Organelle-specific regulation of ferroptosis. Cell Death Differ. 2021;28(10):2843–2856.
  • Mailloux RJ. An Update on Mitochondrial Reactive Oxygen Species Production. Antioxidants (Basel). 2020;9(6):472.
  • Andréasson C, Ott M, Büttner S. Mitochondria orchestrate proteostatic and metabolic stress responses. EMBO Rep. 2019;20(10):e47865.
  • Gan B. Mitochondrial regulation of ferroptosis. J Cell Biol. 2021;220(9):e202105043.
  • Wang YQ, Chang SY, Wu Q, et al. The Protective Role of Mitochondrial Ferritin on Erastin-Induced Ferroptosis. Front Aging Neurosci. 2016;8:308.
  • Tsubaki H, Yanagisawa D, Kageyama Y, Hafiz Abu Baker Z, Mukaisho KI, Tooyama I. Immunohistochemical Analysis of Mitochondrial Ferritin in the Midbrain of Patients with Parkinson’s Disease. Acta Histochem Cytochem. 2023;56(2):21–27.
  • Chan S, Lian Q, Chen MP, et al. Deferiprone inhibits iron overload-induced tissue factor bearing endothelial microparticle generation by inhibition oxidative stress induced mitochondrial injury, and apoptosis. Toxicol Appl Pharmacol. 2018;338:148–158.
  • Alvarez SW, Sviderskiy VO, Terzi EM, et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature. 2017;551(7682):639–643.
  • Mao C, Liu X, Zhang Y, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593(7860):586–590.
  • Gao M, Yi J, Zhu J, et al. Role of Mitochondria in Ferroptosis. Mol Cell. 2019;73(2):354–363.e3.
  • Xiong Y, Ding H, Xu M, Gao J. Protective effects of asiatic acid on rotenone- or H2O2-induced injury in SH-SY5Y cells. Neurochem Res. 2009;34(4):746–754.
  • Chaudhuri AD, Choi DC, Kabaria S, Tran A, Junn E. MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression. J Biol Chem. 2016;291(12):6483–6493.
  • Magalingam KB, Somanath SD, Ramdas P, Haleagrahara N, Radhakrishnan AK. 6-Hydroxydopamine Induces Neurodegeneration in Terminally Differentiated SH-SY5Y Neuroblastoma Cells via Enrichment of the Nucleosomal Degradation Pathway: a Global Proteomics Approach. J Mol Neurosci. 2022;72(5):1026–1046.
  • Nagakannan P, Islam MI, Karimi-Abdolrezaee S, Eftekharpour E. Inhibition of VDAC1 Protects Against Glutamate-Induced Oxytosis and Mitochondrial Fragmentation in Hippocampal HT22 Cells. Cell Mol Neurobiol. 2019;39(1):73–85.
  • Wen S, Aki T, Unuma K, Uemura K. Chemically Induced Models of Parkinson’s Disease: history and Perspectives for the Involvement of Ferroptosis. Front Cell Neurosci. 2020;14:581191.
  • Mustapha M, Mat Taib CN. MPTP-induced mouse model of Parkinson’s disease: a promising direction of therapeutic strategies. Bosn J Basic Med Sci. 2021;21(4):422–433.
  • Tanner CM, Kamel F, Ross GW, et al. Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect. 2011;119(6):866–872.
  • Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem. 2002;277(3):1641–1644.
  • Bus JS, Aust SD, Gibson JE. Paraquat toxicity: proposed mechanism of action involving lipid peroxidation. Environ Health Perspect. 1976;139–146.
  • Fernagut PO, Hutson CB, Fleming SM, et al. Behavioral and histopathological consequences of paraquat intoxication in mice: effects of alpha-synuclein over-expression. Synapse. 2007;61(12):991–1001.
  • Yang WS, Tiffany-Castiglioni E. The bipyridyl herbicide paraquat produces oxidative stress-mediated toxicity in human neuroblastoma SH-SY5Y cells: relevance to the dopaminergic pathogenesis. J Toxicol Environ Heal A. 2005;68(22):1939–1961.
  • Niso-Santano M, González-Polo RA, Bravo-San Pedro JM, et al. Activation of apoptosis signal-regulating kinase 1 is a key factor in paraquat-induced cell death: modulation by the Nrf2/Trx axis. Free Radic Biol Med. 2010;48(10):1370–1381.
  • Cristóvao AC, Choi DH, Baltazar G, Beal MF, Kim YS. The Role of NADPH Oxidase 1-Derived Reactive Oxygen Species in Paraquat-Mediated Dopaminergic Cell Death. Antioxid Redox Sign. 2009;11(9):2105–2118.
  • Castello PR, Drechsel DA, Patel M. Mitochondria are a major source of paraquat-induced reactive oxygen species production in the brain. J Biol Chem. 2007;282(19):14186–14193.
  • Hou LY, Huang RX, Sun FQ, Zhang L, Wang QS. NADPH oxidase regulates paraquat and maneb-induced dopaminergic neurodegeneration through ferroptosis. Toxicology. 2019;417:64–73.
  • Hou LY, Sun FQ, Sun W, Zhang L, Wang QS. Lesion of the Locus Coeruleus Damages Learning and Memory Performance in Paraquat and Maneb-induced Mouse Parkinson’s Disease Model. Neuroscience. 2019;419:129–140.
  • Talpade DJ, Greene JG, Higgins DS, Greenamyre JT. In vivo labeling of mitochondrial complex I (NADH:ubiquinone oxidoreductase) in rat brain using [(3)H]dihydrorotenone. J Neurochem. 2000;75(6):2611–2621.
  • Berry TM, Moustafa AA. A novel treatment strategy to prevent Parkinson’s disease: focus on iron regulatory protein 1 (IRP1). Int J Neurosci. 2023;133(1):67–76.
  • Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci. 2000;3(12):1301–1306.
  • Ferrante RJ, Schulz JB, Kowall NW, Beal MF. Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra. Brain Res. 1997;753(1):157–162.
  • Kabiraj P, Valenzuela CA, Marin JE, et al. The neuroprotective role of ferrostatin-1 under rotenone-induced oxidative stress in dopaminergic neuroblastoma cells. Protein J. 2015;34(5):349–358.
  • Hu CB, Jiang H, Yang Y, et al. DL-3-n-butylphthalide alleviates motor disturbance by suppressing ferroptosis in a rat model of Parkinson’s disease. Neural Regen Res. 2023;18(1):194–199.
  • Avci B, Günaydın C, Külbay M, Kuruca N, Güvenç T, Bilge SS. Neuroprotective effects of sinapic acid involve the iron regulatory role on the rotenone-induced Parkinson’s disease model. Braz J Pharm Sci. 2022;58:e20942.
  • Avci B, Günaydın C, Güvenç T, Yavuz CK, Kuruca N, Bilge SS. Idebenone Ameliorates Rotenone-Induced Parkinson’s Disease in Rats Through Decreasing Lipid Peroxidation. Neurochem Res. 2021;46(3):513–522.
  • Mursaleen L, Noble B, Chan SHY, Somavarapu S, Zariwala MG. N-Acetylcysteine Nanocarriers Protect against Oxidative Stress in a Cellular Model of Parkinson’s Disease. Antioxidants (Basel). 2020;9(7):600.
  • Li H, Shen Y, Xiao H, Sun W. Resveratrol attenuates rotenone-induced inflammation and oxidative stress via STAT1 and Nrf2/Keap1/SLC7A11 pathway in a microglia cell line. Pathol Res Pract. 2021;225:153576.
  • Muñoz-Manchado AB, Villadiego J, Romo-Madero S, et al. Chronic and progressive Parkinson’s disease MPTP model in adult and aged mice. J Neurochem. 2016;136(2):373–387.
  • Zhang QS, Heng Y, Mou Z, Huang JY, Yuan YH, Chen NH. Reassessment of subacute MPTP-treated mice as animal model of Parkinson’s disease. Acta Pharmacol Sin. 2017;38(10):1317–1328.
  • Shi L, Huang C, Luo Q, et al. Clioquinol improves motor and non-motor deficits in MPTP-induced monkey model of Parkinson’s disease through AKT/mTOR pathway. Aging (Albany NY). 2020;12(10):9515–9533.
  • Bai L, Yan F, Deng R, Gu R, Zhang X, Bai J. Thioredoxin-1 Rescues MPP+/MPTP-Induced Ferroptosis by Increasing Glutathione Peroxidase 4. Mol Neurobiol. 2021;58(7):3187–3197.
  • Lin ZH, Liu Y, Xue NJ, et al. Quercetin Protects against MPP+/MPTP-Induced Dopaminergic Neuron Death in Parkinson’s Disease by Inhibiting Ferroptosis. Oxid Med Cell Longev. 2022;2022:7769355.
  • Ungerstedt U, Ljungberg T, Steg G. Behavioral, physiological, and neurochemical changes after 6-hydroxydopamine-induced degeneration of the nigro-striatal dopamine neurons. Mol Neurobiol. 1974;421–426.
  • Bastías-Candia S, Zolezzi JM, Inestrosa NC. Revisiting the Paraquat-Induced Sporadic Parkinson’s Disease-Like Model. Mol Neurobiol. 2019;56(2):1044–1055.
  • Cheng H, Chen Y, Yang HF, Tang X, Zhu WY. Protective Effects of Maprotiline in 6-Hydroxydopamine (6-OHDA)-Induced Ferroptosis in Neuronal Cells. Biomed Nanotechnol. 2022;18(11):2592–2598.
  • Sun Y, He L, Wang W, et al. Activation of Atg7-dependent autophagy by a novel inhibitor of the Keap1-Nrf2 protein-protein interaction from Penthorum chinense Pursh. attenuates 6-hydroxydopamine-induced ferroptosis in zebrafish and dopaminergic neurons. Food Funct. 2022;13(14):7885–7900.
  • Gutbier S, Kyriakou S, Schildknecht S, et al. Design and evaluation of bi-functional iron chelators for protection of dopaminergic neurons from toxicants. Arch Toxicol. 2020;94(9):3105–3123.
  • Wang L, An H, Yu F, et al. The neuroprotective effects of paeoniflorin against MPP+-induced damage to dopaminergic neurons via the Akt/Nrf2/GPX4 pathway. J Chem Neuroanat. 2022;122:102103.
  • Liu L, Yang S, Wang H. α-Lipoic acid alleviates ferroptosis in the MPP+ -induced PC12 cells via activating the PI3K/Akt/Nrf2 pathway. Cell Biol Int. 2021;45(2):422–431.
  • Xi J, Zhang Z, Wang Z, et al. Hinokitiol functions as a ferroptosis inhibitor to confer neuroprotection. Free Radic Biol Med. 2022;190:202–215.
  • Jiang Y, Xie G, Alimujiang A, et al. Protective Effects of Querectin against MPP+-Induced Dopaminergic Neurons Injury via the Nrf2 Signaling Pathway. Front Biosci. 2023;28(3):42.
  • Bellavite P. Neuroprotective Potentials of Flavonoids: experimental Studies and Mechanisms of Action. Antioxidants (Basel). 2023;12(2):280.
  • Song LM, Xiao ZX, Zhang N, et al. Apoferritin improves motor deficits in MPTP-treated mice by regulating brain iron metabolism and ferroptosis. iScience. 2021;24(5):102431.
  • Zilka O, Poon JF, Pratt DA. Radical-Trapping Antioxidant Activity of Copper and Nickel Bis(Thiosemicarbazone) Complexes Underlies Their Potency as Inhibitors of Ferroptotic Cell Death. J Am Chem Soc. 2021;143(45):19043–19057.
  • Tourville A, Viguier S, González-Lizárraga F, et al. Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives. Antioxidants (Basel). 2023;12(3):575.
  • Wang Y, Wu S, Li Q, et al. Epigallocatechin-3-gallate: a phytochemical as a promising drug candidate for the treatment of Parkinson’s disease. Front Pharmacol. 2022;13:977521.
  • Chen D, Kanthasamy AG, Reddy MB. EGCG Protects against 6-OHDA-Induced Neurotoxicity in a Cell Culture Model. Parkinsons Dis. 2015;2015:843906.
  • Hirata Y, Yamada C, Ito Y, et al. Novel oxindole derivatives prevent oxidative stress-induced cell death in mouse hippocampal HT22 cells. Neuropharmacology. 2018;135:242–252.
  • Nebie O, Devos D, Vingtdeux V, et al. The neuroprotective activity of heat-treated human platelet lysate biomaterials manufactured from outdated pathogen-reduced (amotosalen/UVA) platelet concentrates. J Biomed Sci. 2019;26(1):89.
  • Gouel F, Do Van B, Chou ML, et al. The protective effect of human platelet lysate in models of neurodegenerative disease: involvement of the Akt and MEK pathways. J Tissue Eng Regen Med. 2017;11(11):3236–3240.
  • Zhao Y, Zhang J, Zhang Y, et al. Proteomic Analysis of Protective Effects of Dl-3-n-Butylphthalide against mpp + -Induced Toxicity via downregulating P53 pathway in N2A Cells. Proteome Sci. 2023;21(1):1.
  • Grolez G, Moreau C, Sablonnière B, et al. Ceruloplasmin activity and iron chelation treatment of patients with Parkinson’s disease. BMC Neurol. 2015;15:74.
  • Cabantchik ZI, Munnich A, Youdim MB, Devos D. Regional siderosis: a new challenge for iron chelation therapy. Front Pharmacol. 2013;4:167. doi:10.3389/fphar.2013.00167
  • Devos D, Labreuche J, Rascol O, et al. Trial of Deferiprone in Parkinson’s Disease. N Engl J Med. 2022;387(22):2045–2055. doi:10.1056/NEJMoa2209254
  • Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002;59(10):1541–1550.
  • Seet RC, Lim EC, Tan JJ, et al. Does high-dose coenzyme Q10 improve oxidative damage and clinical outcomes in Parkinson’s disease?. Antioxid Redox Signal. 2014;21(2):211–217.
  • Storch A, Jost WH, Vieregge P, et al. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol. 2007;64(7):938–944.
  • Enns GM, Kinsman SL, Perlman SL, et al. Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol Genet Metab. 2012;105(1):91–102.
  • Mischley LK, Lau RC, Shankland EG, Wilbur TK, Padowski JM. Phase IIb Study of Intranasal Glutathione in Parkinson’s Disease. J Parkinsons Dis. 2017;7(2):289–299.
  • Beal MF, Oakes D; Parkinson Study Group QEI. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol. 2014;71(5):543–552.
  • Investigators NN-P. A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease. Neurology. 2007;68(1):20–28.