Ferroptosis in Parkinson’s disease: glia–neuron crosstalk

Iron uptake, storage, efflux, and utilization are essential for maintaining iron homeostasis. Abnormal expression of proteins involved in these processes related to iron homeostasis may cause iron overload and induce subsequent ferroptosis, which is associated with the pathogenesis of neurodegenerative disease.Crosstalk between glia and neurons underlies the ferroptotic alterations in DA neurons and form a vicious circle in promoting PD pathogenesis.Possible mechanisms of iron transfer between glia and neurons include exosomes and tunneling nanotubes. They may determine the efficacy of ferroptosis inhibitors and provide a clue for exploring novel therapeutic interventions for PD.Joint medications with ferroptosis inhibitors and anti-inflammatory medicines may provide a potential strategy for the treatment of PD and related neurodegenerative diseases. Parkinson’s disease (PD) is characterized by dopaminergic (DA) neuron loss and the formation of cytoplasmic protein inclusions. Although the exact pathogenesis of PD is unknown, iron dyshomeostasis has been proposed as a potential contributing factor. Emerging evidence suggests that glial cell activation plays a pivotal role in ferroptosis and subsequent neurodegeneration. We review the association between iron deposition, glial activation, and neuronal death, and discuss whether and how ferroptosis affects α-synuclein aggregation and DA neuron loss. We examine the possible roles of different types of glia in mediating ferroptosis in neurons. Lastly, we review current PD clinical trials targeting iron homeostasis. Although clinical trials are already evaluating ferroptosis modulation in PD, much remains unknown about metal ion metabolism and regulation in PD pathogenesis. Parkinson’s disease (PD) is characterized by dopaminergic (DA) neuron loss and the formation of cytoplasmic protein inclusions. Although the exact pathogenesis of PD is unknown, iron dyshomeostasis has been proposed as a potential contributing factor. Emerging evidence suggests that glial cell activation plays a pivotal role in ferroptosis and subsequent neurodegeneration. We review the association between iron deposition, glial activation, and neuronal death, and discuss whether and how ferroptosis affects α-synuclein aggregation and DA neuron loss. We examine the possible roles of different types of glia in mediating ferroptosis in neurons. Lastly, we review current PD clinical trials targeting iron homeostasis. Although clinical trials are already evaluating ferroptosis modulation in PD, much remains unknown about metal ion metabolism and regulation in PD pathogenesis. PD is one of the most common neurodegenerative diseases. Two major pathological hallmarks of PD are the progressive loss of DA neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies and Lewy neurites. Misfolded and aggregated α-synuclein (α-syn; see Glossary) is the primary protein component of Lewy pathology [1.Jankovic J. et al.Parkinson's disease: etiopathogenesis and treatment.J. Neurol. Neurosurg. Psychiatry. 2020; 91: 795-808Crossref PubMed Scopus (98) Google Scholar]. To date, relatively little is known of PD pathogenesis, although potential disease mechanisms include immune activation, mitochondrial dysfunction, lipid dyshomeostasis, and metal ion imbalance [1.Jankovic J. et al.Parkinson's disease: etiopathogenesis and treatment.J. Neurol. Neurosurg. Psychiatry. 2020; 91: 795-808Crossref PubMed Scopus (98) Google Scholar]. Notably, glia activation is evident during the onset and progression of PD [2.Kam T.I. et al.Microglia and astrocyte dysfunction in Parkinson's disease.Neurobiol. Dis. 2020; 144105028Crossref PubMed Scopus (55) Google Scholar]. Activated glia may act as 'double-edged swords' because they can exert neuroprotective effects by releasing neurotrophic factors and phagocytosis, while mediating neuronal damage by releasing proinflammatory cytokines [3.Liddelow S.A. et al.Neurotoxic reactive astrocytes are induced by activated microglia.Nature. 2017; 541: 481-487Crossref PubMed Scopus (2734) Google Scholar]. Brain imaging and pathological studies have shown correlations between iron deposition in the SNpc of PD patient brains and DA neuronal loss [4.Depierreux F. et al.Parkinson's disease multimodal imaging: F-DOPA PET, neuromelanin-sensitive and quantitative iron-sensitive MRI.NPJ Parkinson's Dis. 2021; 7: 57Crossref PubMed Scopus (2) Google Scholar,5.Biondetti E. et al.The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson's disease.Brain. 2021; 144: 3114-3125Crossref PubMed Scopus (5) Google Scholar], indicating that imbalance of iron homeostasis may be a factor closely associated with neuronal death in PD. This type of iron-dependent cell death is termed ferroptosis [6.Dixon S.J. et al.Ferroptosis: an iron-dependent form of nonapoptotic cell death.Cell. 2012; 149: 1060-1072Abstract Full Text Full Text PDF PubMed Scopus (3929) Google Scholar]. Excessive iron accumulation in cultured DA cells can trigger ferroptosis [7.Zhang P. 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: 227-234Crossref PubMed Scopus (41) Google Scholar]. Ferroptosis was also reported in SH-SY5Y (human neuroblastoma) cells exposed to the DA neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) [8.Sun Y. et al.Activation of p62–Keap1–Nrf2 pathway protects 6-hydroxydopamine-induced ferroptosis in dopaminergic cells.Mol. Neurobiol. 2020; 57: 4628-4641Crossref PubMed Scopus (27) Google Scholar,9.Ito K. et al.MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells.Cell Death Discov. 2017; 3: 17013Crossref PubMed Scopus (51) Google Scholar]. Similar phenomena were observed in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD mouse models [10.Do Van B. et al.Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC.Neurobiol. Dis. 2016; 94: 169-178Crossref PubMed Scopus (266) Google Scholar]. Furthermore, ferroptosis inhibitors can rescue the DA neuron death in PD [10.Do Van B. et al.Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC.Neurobiol. Dis. 2016; 94: 169-178Crossref PubMed Scopus (266) Google Scholar]. Both glial cell activation and iron dyshomeostasis are crucial events in PD pathogenesis. They can reciprocally influence each other and act as 'partners in crime' in boosting DA neuron degeneration [11.Fernández-Mendívil C. et al.Protective role of microglial HO-1 blockade in aging: implication of iron metabolism.Redox Biol. 2021; 38101789Crossref PubMed Scopus (21) Google Scholar,12.Zhu Y. et al.Iron accumulation and microglia activation contribute to substantia nigra hyperechogenicity in the 6-OHDA-induced rat model of Parkinson's disease.Parkinsonism Relat. Disord. 2017; 36: 76-82Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Activated glia promote iron dyshomeostasis, which aggravates microglial activation [13.Novgorodov S.A. et al.Acid sphingomyelinase promotes mitochondrial dysfunction due to glutamate-induced regulated necrosis.J. Lipid Res. 2018; 59: 312-329Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. These findings suggest that the association between iron deposition-induced ferroptosis, glia activation, and neurodegeneration could potentially underlie the pathogenesis of PD. To address the regulatory mechanisms of ferroptosis in neurons, especially the role of glia, we focus on the involvement of different glial cells in ferroptosis in PD. We first address the major phenomena of iron metabolism and the process and regulation of ferroptosis, with a particular focus on their impact on PD pathologies. We also discuss how different glia may regulate iron homeostasis and oxidative stress to modulate the process of DA neuron ferroptosis. Lastly, we review recent and ongoing clinical trials that leverage ferroptosis modulation for the treatment of PD. Ferroptosis is an iron-dependent form of regulated cell death that is initiated by abnormal iron metabolism and severe lipid peroxidation, leading to oxidative stress and cell death [6.Dixon S.J. et al.Ferroptosis: an iron-dependent form of nonapoptotic cell death.Cell. 2012; 149: 1060-1072Abstract Full Text Full Text PDF PubMed Scopus (3929) Google Scholar]. Unlike apoptosis and other forms of cell death, ferroptosis-induced cytological changes include cell volume shrinkage and the disappearance of mitochondria cristae, increased mitochondrial membrane density, and outer mitochondrial membrane rupture [6.Dixon S.J. et al.Ferroptosis: an iron-dependent form of nonapoptotic cell death.Cell. 2012; 149: 1060-1072Abstract Full Text Full Text PDF PubMed Scopus (3929) Google Scholar,14.Friedmann Angeli J.P. et al.Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice.Nat. Cell Biol. 2014; 16: 1180-1191Crossref PubMed Scopus (1148) Google Scholar]. However, the nuclei of ferroptotic cells maintain their structural integrity, and there is no cytoplasmic or organelle swelling, plasma membrane rupture, or formation of apoptotic bodies [6.Dixon S.J. et al.Ferroptosis: an iron-dependent form of nonapoptotic cell death.Cell. 2012; 149: 1060-1072Abstract Full Text Full Text PDF PubMed Scopus (3929) Google Scholar]. Ferroptosis is probably regulated by multiple pathways, including iron metabolism, oxidative stress, and cytotoxic amino acid metabolism (Figure 1). In addition, susceptibility to ferroptosis may also be affected by other pathways such as ferroptosis suppressor protein 1 (FSP1)–coenzyme Q10 (CoQ10) [15.Bersuker K. et al.The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.Nature. 2019; 575: 688-692Crossref PubMed Scopus (627) Google Scholar]. Although the exact mechanisms of neuronal ferroptosis remain obscure, the participation of non-neuronal cell types such as glia is essential in mediating iron toxicity to neurons. Several studies have demonstrated the crucial effects of glia on regulating ferroptosis in DA neurons. For example, it is known that heme oxygenase 1 (HO-1), an inducible enzyme, catabolizes the heme group into carbon monoxide and biliverdin, which in turn converts to bilirubin and labile iron. In a model of aging in wild-type mice, HO-1 was upregulated accompanied by increased microglial activation, iron deposition, and ferroptosis. By contrast, cell-specific knockout of the Hmox1 gene in mice and treatment with iron chelator deferoxamine (DFX) showed preventive effects against ferroptosis [11.Fernández-Mendívil C. et al.Protective role of microglial HO-1 blockade in aging: implication of iron metabolism.Redox Biol. 2021; 38101789Crossref PubMed Scopus (21) Google Scholar]. Although ferroptosis was first reported in cancer cells [6.Dixon S.J. et al.Ferroptosis: an iron-dependent form of nonapoptotic cell death.Cell. 2012; 149: 1060-1072Abstract Full Text Full Text PDF PubMed Scopus (3929) Google Scholar], it was also found to be involved in DA neuron death in PD [10.Do Van B. et al.Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC.Neurobiol. Dis. 2016; 94: 169-178Crossref PubMed Scopus (266) Google Scholar]. Several mutations in ferroptosis genes have been linked to PD (Table 1), including DJ-1, autosomal recessive PD gene, that encodes a negative modulator of ferroptosis [16.Cao J. et al.DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase.Nat. Commun. 2020; 11: 1251Crossref PubMed Scopus (50) Google Scholar]. Moreover, the characteristics of ferroptosis induction are highly consistent with the pathological changes observed in PD patients, including increased iron content [4.Depierreux F. et al.Parkinson's disease multimodal imaging: F-DOPA PET, neuromelanin-sensitive and quantitative iron-sensitive MRI.NPJ Parkinson's Dis. 2021; 7: 57Crossref PubMed Scopus (2) Google Scholar,5.Biondetti E. et al.The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson's disease.Brain. 2021; 144: 3114-3125Crossref PubMed Scopus (5) Google Scholar], lipid peroxidation [17.Sun W.Y. et al.Phospholipase iPLA(2)β averts ferroptosis by eliminating a redox lipid death signal.Nat. Chem. Biol. 2021; 17: 465-476Crossref PubMed Scopus (38) Google Scholar, 18.de Farias C.C. et al.Highly specific changes in antioxidant levels and lipid peroxidation in Parkinson's disease and its progression: disease and staging biomarkers and new drug targets.Neurosci. Lett. 2016; 617: 66-71Crossref PubMed Scopus (58) Google Scholar, 19.Vida C. et al.Lymphoproliferation impairment and oxidative stress in blood cells from early Parkinson's disease patients.Int. J. Mol. Sci. 2019; 20: 771Crossref Scopus (12) Google Scholar], and defects in the antioxidant system such as decreased levels of cystine/glutamate antiporter (xCT) [20.Vallerga C.L. et al.Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease.Nat. Commun. 2020; 11: 1238Crossref PubMed Scopus (24) Google Scholar], glutathione (GSH) [21.Venkateshappa C. et al.Increased oxidative damage and decreased antioxidant function in aging human substantia nigra compared to striatum: implications for Parkinson’s disease.Neurochem. Res. 2012; 37: 358-369Crossref PubMed Scopus (111) Google Scholar], DJ-1 (that maintains cysteine and GSH biosynthesis) [16.Cao J. et al.DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase.Nat. Commun. 2020; 11: 1251Crossref PubMed Scopus (50) Google Scholar], and CoQ10 [22.Mischley L.K. et al.Coenzyme Q10 deficiency in patients with Parkinson’s disease.J. Neurol. Sci. 2012; 318: 72-75Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. Furthermore, ferroptosis was observed in different PD cellular and animal models such as SH-SY5Y cells treated with MPP+ and 6-OHDA, and MPTP-lesioned mice [8.Sun Y. et al.Activation of p62–Keap1–Nrf2 pathway protects 6-hydroxydopamine-induced ferroptosis in dopaminergic cells.Mol. Neurobiol. 2020; 57: 4628-4641Crossref PubMed Scopus (27) Google Scholar, 9.Ito K. et al.MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells.Cell Death Discov. 2017; 3: 17013Crossref PubMed Scopus (51) Google Scholar, 10.Do Van B. et al.Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC.Neurobiol. Dis. 2016; 94: 169-178Crossref PubMed Scopus (266) Google Scholar]. Furthermore, inhibition of ferroptosis by using ferrostatin-1 (Fer-1) can alleviate locomotor behavioral deficits and rescue tyrosine hydroxylase (TH) neuronal loss in MPTP-induced PD mice [23.Bai L. et al.Thioredoxin-1 rescues MPP+/MPTP-induced ferroptosis by increasing glutathione peroxidase 4.Mol. Neurobiol. 2021; 58: 3187-3197Crossref PubMed Scopus (6) Google Scholar]. A very recent study with combined MRI imaging, quantitative susceptibility mapping (QSM), and regional gene profiling in a cohort of PD (96) patients and 35 control subjects showed significantly increased cortical iron deposition in PD compared to the control subjects. Gene expression profiling has also demonstrated that genes related to heavy metal detoxification and synaptic function are predominantly and differentially expressed in astrocytes and glutamatergic neurons in PD patients [24.Thomas G.E.C. et al.Regional brain iron and gene expression provide insights into neurodegeneration in Parkinson’s disease.Brain. 2021; 144: 1787-1798Crossref PubMed Scopus (7) Google Scholar], suggesting regional and selective vulnerabilities in relation to iron accumulation in PD. Although this evidence suggests a prominent role for iron homeostasis and ferroptosis in mediating neuron death in PD, how these contribute to each other and lead to neurodegeneration largely remains unknown. Further studies, particularly on the biological processes involved in iron deposition and associated cell death, are urgently needed.Table 1Ferroptosis-related genes in PDaAbbreviations: FTH1, ferritin heavy chain 1; IL-13, interleukin-13; IL-13Rα1, interleukin-13 receptor α1; iPLA2β, Ca2+-independent phospholipase A2β (encoded by PLA2G6/PNPLA9); SLC7A11, solute carrier family 7 member 11; SNX5, sorting nexin 5; Trx-1, thioredoxin-1.GeneFunctionRefsACSL4ACSL4 converts free fatty acids into fatty-CoA esters[69.Song L.M. et al.Apoferritin improves motor deficits in MPTP-treated mice by regulating brain iron metabolism and ferroptosis.iScience. 2021; 24: 102431Abstract Full Text Full Text PDF PubMed Google Scholar]DJ1DJ-1 maintains cysteine and GSH biosynthesis through the trans-sulfuration pathway[16.Cao J. et al.DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase.Nat. Commun. 2020; 11: 1251Crossref PubMed Scopus (50) Google Scholar,92.Jiang L. et al.The C terminus of DJ-1 determines its homodimerization, MGO detoxification activity and suppression of ferroptosis.Acta Pharmacol. Sin. 2021; 42: 1150-1159Crossref PubMed Scopus (5) Google Scholar]FTH1FTH1 inhibits ferroptosis through ferritinophagy in the 6-OHDA model of PD[93.Tian Y. et al.FTH1 Inhibits ferroptosis through ferritinophagy in the 6-OHDA model of Parkinson’s disease.Neurotherapeutics. 2020; 17: 1796-1812Crossref PubMed Scopus (37) Google Scholar]GPX4GPX4 reduces membrane phospholipid hydroperoxides and suppresses ferroptosis[10.Do Van B. et al.Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC.Neurobiol. Dis. 2016; 94: 169-178Crossref PubMed Scopus (266) Google Scholar,94.Hambright W.S. et al.Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration.Redox Biol. 2017; 12: 8-17Crossref PubMed Scopus (300) Google Scholar]IL13,IL13RA1The interaction of IL-13 with IL-13Rα1 increases the susceptibility of mouse DA neurons to oxidative stress[95.Aguirre C.A. et al.Two single nucleotide polymorphisms in IL13 and IL13RA1 from individuals with idiopathic Parkinson’s disease increase cellular susceptibility to oxidative stress.Brain Behav. Immun. 2020; 88: 920-924Crossref PubMed Scopus (3) Google Scholar]PLA2G6Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal[17.Sun W.Y. et al.Phospholipase iPLA(2)β averts ferroptosis by eliminating a redox lipid death signal.Nat. Chem. Biol. 2021; 17: 465-476Crossref PubMed Scopus (38) Google Scholar]miR-335miR-335 enhances ferroptosis through the degradation of FTH1[96.Li X. et al.miR-335 promotes ferroptosis by targeting ferritin heavy chain 1 in in vivo and in vitro models of Parkinson's disease.Int. J. Mol. Med. 2021; 47: 61Crossref PubMed Scopus (5) Google Scholar]NRF2Nrf2 is directly or indirectly involved in modulating ferroptosis, including metabolism of GSH, iron, and lipids, as well as mitochondrial function[72.Ishii T. et al.Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis.Free Radic. Biol. Med. 2019; 133: 169-178Crossref PubMed Scopus (62) Google Scholar]TP53Inhibition of p53 upregulates SLC7A11 and GPX4[97.Li S. et al.p53-mediated ferroptosis is required for 1-methyl-4-phenylpyridinium-induced senescence of PC12 cells.Toxicol. in Vitro. 2021; 73105146Crossref Scopus (3) Google Scholar]SQSTM1High p62 expression inhibits ferroptosis by promoting Nrf2 nuclear transfer and upregulating HO-1 expression[8.Sun Y. et al.Activation of p62–Keap1–Nrf2 pathway protects 6-hydroxydopamine-induced ferroptosis in dopaminergic cells.Mol. Neurobiol. 2020; 57: 4628-4641Crossref PubMed Scopus (27) Google Scholar]SLC7A11Codes for xCT that regulates GSH levels[20.Vallerga C.L. et al.Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease.Nat. Commun. 2020; 11: 1238Crossref PubMed Scopus (24) Google Scholar]SNX5Silencing of SNX5 lowers the level of ferroptosis in 6-OHDA-induced PC12 cells[98.Si W. et al.Super-enhancer-driven sorting nexin 5 expression promotes dopaminergic neuronal ferroptosis in Parkinson's disease models.Biochem. Biophys. Res. Commun. 2021; 567: 35-41Crossref PubMed Scopus (6) Google Scholar]Trx1Trx-1 overexpression inhibits the decrease of GPX4 and GSH and the increase of ROS[23.Bai L. et al.Thioredoxin-1 rescues MPP+/MPTP-induced ferroptosis by increasing glutathione peroxidase 4.Mol. Neurobiol. 2021; 58: 3187-3197Crossref PubMed Scopus (6) Google Scholar]a Abbreviations: FTH1, ferritin heavy chain 1; IL-13, interleukin-13; IL-13Rα1, interleukin-13 receptor α1; iPLA2β, Ca2+-independent phospholipase A2β (encoded by PLA2G6/PNPLA9); SLC7A11, solute carrier family 7 member 11; SNX5, sorting nexin 5; Trx-1, thioredoxin-1. Open table in a new tab α-Syn aggregation in neurons and glia is a key pathological feature of PD. Different forms of aggregated α-syn can be spread from one cell to another from the peripheral tissues to the brain or within the brain [25.Liu D. et al.Differential seeding and propagating efficiency of α-synuclein strains generated in different conditions.Transl. Neurodegener. 2021; 10: 20Crossref PubMed Scopus (3) Google Scholar, 26.Hansen C. et al.α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells.J. Clin. Invest. 2011; 121: 715-725Crossref PubMed Scopus (604) Google Scholar, 27.Luk K.C. et al.Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice.Science. 2012; 338: 949-953Crossref PubMed Scopus (1446) Google Scholar]. Postmortem analyses from PD patients showed the coexistence of iron and α-syn in Lewy bodies in midbrain [28.Castellani R.J. et al.Sequestration of iron by Lewy bodies in Parkinson’s disease.Acta Neuropathol. 2000; 100: 111-114Crossref PubMed Scopus (191) Google Scholar]. Iron accumulates in the substantial nigra of the midbrain and colocalizes with α-syn [29.Ayton S. et al.Nigral iron elevation is an invariable feature of Parkinson's disease and is a sufficient cause of neurodegeneration.Biomed. Res. 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Iron also takes part in post-transcriptional regulation [32.Febbraro F. et al.α-Synuclein expression is modulated at the translational level by iron.Neuroreport. 2012; 23: 576-580Crossref PubMed Scopus (77) Google Scholar] and post-translational modification of α-syn [33.Wang R. et al.Iron-induced oxidative stress contributes to α-synuclein phosphorylation and up-regulation via polo-like kinase 2 and casein kinase 2.Neurochem. Int. 2019; 125: 127-135Crossref PubMed Scopus (21) Google Scholar]. α-Syn mRNA contains an iron response element (IRE) within its 5′-untranslated region (UTR) [34.Friedlich A.L. et al.The 5′-untranslated region of Parkinson’s disease alpha-synuclein messengerRNA contains a predicted iron responsive element.Mol. Psychiatry. 2007; 12: 222-223Crossref PubMed Scopus (134) Google Scholar]. In SH-SY5Y and N2A (mouse neuroblastoma) cells, the addition of iron ions can accelerate α-syn spreading between cells and promote α-syn aggregation. The α-syn aggregates formed can be cytotoxic, leading to increased reactive oxygen species (ROS) production and cell death [35.Li Y. et al.Copper and iron ions accelerate the prion-like propagation of α-synuclein: a vicious cycle in Parkinson’s disease.Int. J. Biol. Macromol. 2020; 163: 562-573Crossref PubMed Scopus (15) Google Scholar]. Iron depletion in HEK293 cells leads to reduced α-syn translation [32.Febbraro F. et al.α-Synuclein expression is modulated at the translational level by iron.Neuroreport. 2012; 23: 576-580Crossref PubMed Scopus (77) Google Scholar]. In an adeno-associated virus (AAV) α-syn-overexpression rat model, chronic intranasal administration of an iron chelator deferoxamine (DFO) was found to reduce iron levels and alleviate motor defects and α-syn pathology [36.Febbraro F. et al.Chronic intranasal deferoxamine ameliorates motor defects and pathology in the α-synuclein rAAV Parkinson's model.Exp. Neurol. 2013; 247: 45-58Crossref PubMed Scopus (40) Google Scholar]. Intranasal DFO can also improve memory in healthy wild-type mice [37.Fine J.M. et al.Intranasal deferoxamine can improve memory in healthy C57 mice, suggesting a partially non-disease-specific pathway of functional neurologic improvement.Brain Behav. 2020; 10e01536Crossref PubMed Scopus (6) Google Scholar]. The data indicate that iron may play a role in α-syn aggregation and contribute to cell death. Conversely, α-Syn can also modulate iron homeostasis. Overexpression of α-syn in rat primary midbrain neurons results in iron overload [38.Ortega R. et al.α-Synuclein over-expression induces increased iron accumulation and redistribution in iron-exposed neurons.Mol. Neurobiol. 2016; 53: 1925-1934Crossref PubMed Scopus (51) Google Scholar], and the ferrireductase activity of α-syn can increase intracellular ferrous iron content in SH-SY5Y cells [39.Davies P. et al.Alpha-synuclein is a cellular ferrireductase.PLoS One. 2011; 6e15814Crossref Google Scholar]. A recent study found that ferroptosis inhibitors could prevent the interaction between α-syn aggregates and cell membranes in induced pluripotent stem cell (iPSC)-derived neurons with triplication of the SNCA gene, and led to reduced accumulation of iron-dependent free radicals and further prevented neuronal death [40.Angelova P.R. et al.Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation.Cell Death Differ. 2020; 27: 2781-2796Crossref PubMed Scopus (44) Google Scholar]. Evidence obtained from cellular and animal models and PD patients suggests a close association between iron accumulation and α-syn protein turnover, including expression, accumulation, aggregation, and degradation. However, in this potentially vicious circle the causal relationship between the two remains unclear. Although the human and in vivo data are still insufficient, considering that α-syn is the primary component for PD protein pathology, normal iron metabolism may be a key element in regulating the pathological progression of PD, and targeting iron homeostasis may have therapeutic potential. Glial activation is involved in the onset and progression of PD through various pathways (Figure 2). Large numbers of activated microglia were found around the degenerated DA neurons in SN in PD patient brains [41.Imamura K. et al.Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains.Acta Neuropathol. 2003; 106: 518-526Crossref PubMed Scopus (480) Google Scholar]. Reactive astrocytes were also detected in autopsies of PD patient brains, accompanied by the formation of α-syn inclusions in neurons [42.Braak H. et al.Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease.Acta Neuropathol. 2007; 114: 231-241Crossref PubMed Scopus (261) Google Scholar]. Activated glia can induce neuronal death in vitro by releasing proinflammatory factors, nitric oxide (NO), ROS, and glutamate [3.Liddelow S.A. et al.Neurotoxic reactive astrocytes are induced by activated microglia.Nature. 2017; 541: 481-487Crossref PubMed Scopus (2734) Google Scholar,43.Subhramanyam C.S. et al.Microglia-mediated neuroinflammation in neurodegenerative diseases.Semin. Cell Dev. Biol. 2019; 94: 112-120Crossref PubMed Scopus (206) Google Scholar]. PD-associated gene leucine-rich repeat kinase 2 (LRRK2) is highly expressed in oligodendrocytes, especially in the precursor cells (OPCs) [44.Agarwal D. et al.A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders.Nat. Commun. 2020; 11: 4183Crossref PubMed Scopus (44) Google Scholar,45.Bryois J. et al.Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease.Nat. Genet. 2020; 52: 482-493Crossref PubMed Scopus (74) Google Scholar]. Different types of glia may contribute to PD pathogenesis via different pathways such as demyelination and cytokine release. Upon activation, they may also induce neuronal ferroptosis by disrupting iron homeostasis, altering amino acid metabolism, and increasing oxidative stress. Studies have shown that microglia play a role in regulating iron homeostasis in neuronal networks. First, iron can accumulate in activated microglia, resulting in increased iron deposition in the central nervous system (CNS) [30.Guo J.J. 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: 81Crossref PubMed Scopus (8) Google Scholar,46.Kenkhuis B. et al.Iron loading is a prominent feature of activated microglia in Alzheimer's disease patients.Act