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New Insights into the Role of Ferritin in Iron Homeostasis and Neurodegenerative Diseases

Molecular Neurobiology volume 58, pages 2812–2823 (2021)Cite this article

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Abstract

Growing evidence has indicated that iron deposition is one of the key factors leading to neuronal death in the neurodegenerative diseases. Ferritin is a hollow iron storage protein composed of 24 subunits of two types, ferritin heavy chain (FTH) and ferritin light chain (FTL), which plays an important role in maintaining iron homeostasis. Recently, the discovery of extracellular ferritin and ferritin in exosomes indicates that ferritin might be not only an iron storage protein within the cell, but might also be an important factor in the regulation of tissue and body iron homeostasis. In this review, we first described the structural characteristics, regulation and the physiological functions of ferritin. Secondly, we reviewed the current evidence concerning the mechanisms underlying the secretion of ferritin and the possible role of secreted ferritin in the brain. Then, we summarized the relationship between ferritin and the neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD) and neuroferritinopathy (NF). Given the importance and relationship between iron and neurodegenerative diseases, understanding the role of ferritin in the brain can be expected to contribute to our knowledge of iron dysfunction and neurodegenerative diseases.

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Abbreviations

3′-UTR:

3′-untranslated region

6-OHDA:

6-Hydroxydopamine

Aβ:

Amyloid-β

ALS:

Amyotrophic lateral sclerosis

AD:

Alzheimer’s disease

APP:

Amyloid-β protein precursor

BBB:

Blood-brain barrier

CSF:

Cerebrospinal fluid

DA:

Dopamine

DMT1:

Divalent metal transporter 1

eIF3:

Eukaryotic translation initiation factor 3

EpRE/ARE:

Electrophile/antioxidant-responsive element

Erk:

Extracellular signal-regulated kinase

FPN1:

Ferroportin 1

FTH:

Ferritin heavy chain

FTL:

Ferritin light chain

FtMt:

Mitochondrial ferritin

IL:

Interleukin

IRE:

Iron-responsive element

IRP:

Iron-regulatory protein

Lf:

Lactoferrin

LfR:

Lactoferrin receptor

LIP:

Labile iron pool

JNK:

c-Jun N-terminal kinase

MS:

Multiple sclerosis

NBIA:

Neurodegeneration with brain iron accumulation

NCOA4:

Nuclear receptor coactivator-4

NF:

Neuroferritinopathy

NF-κB:

Nuclear factor kappa B

NM:

Neuromelanin

Nrf2:

NF-E2-related factor 2

PD:

Parkinson’s disease

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SCARA5:

Scavenger receptor class A member 5

SF:

Synovial fluid

SN:

Substantia nigra

SNAP:

Synaptosomal-associated protein

SNpc:

Substantia nigra pars compacta

SP:

Senile plaques

STX:

Syntaxin

Tf:

Transferrin

TfR:

Transferrin receptor

Tim:

T cell immunoglobulin and mucin domain-containing protein

TNF-α:

Tumor necrosis factor-α

TRIM16:

Tripartite motif-containing protein 16

References

  1. Stehling O, Wilbrecht C, Lill R (2014) Mitochondrial iron-sulfur protein biogenesis and human disease. Biochimie 100:61–77. https://doi.org/10.1016/j.biochi.2014.01.010

    Article  CAS  PubMed  Google Scholar 

  2. Silva B, Faustino P (2015) An overview of molecular basis of iron metabolism regulation and the associated pathologies. Biochim Biophys Acta 1852(7):1347–1359. https://doi.org/10.1016/j.bbadis.2015.03.011

    Article  CAS  PubMed  Google Scholar 

  3. Zhang Y, Li H, Zhang C, An X, Liu L, Stubbe J, Huang M (2014) Conserved electron donor complex Dre2-Tah18 is required for ribonucleotide reductase metallocofactor assembly and DNA synthesis. Proc Natl Acad Sci U S A 111(17):E1695–E1704. https://doi.org/10.1073/pnas.1405204111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Netz DJ, Stith CM, Stümpfig M, Köpf G, Vogel D, Genau HM, Stodola JL, Lill R et al (2011) Eukaryotic DNA polymerases require an iron-sulfur cluster for the formation of active complexes. Nat Chem Biol 8(1):125–132. https://doi.org/10.1038/nchembio.721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Levi S, Rovida E (2009) The role of iron in mitochondrial function. Biochim Biophys Acta 1790(7):629–636. https://doi.org/10.1016/j.bbagen.2008.09.008

    Article  CAS  PubMed  Google Scholar 

  6. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L (2014) The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 13(10):1045–1060. https://doi.org/10.1016/s1474-4422(14)70117-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Grubic Kezele T, Curko-Cofek B (2020) Age-related changes and sex-related differences in brain iron metabolism. Nutrients 12(9). https://doi.org/10.3390/nu12092601

  8. Wang L, Li C, Chen X, Li S, Shang H (2020) Abnormal serum iron-status indicator changes in amyotrophic lateral sclerosis (ALS) patients: a meta-analysis. Front Neurol 11:380. https://doi.org/10.3389/fneur.2020.00380

    Article  PubMed  PubMed Central  Google Scholar 

  9. Li Y, Huang X, Wang J, Huang R, Wan D (2020) Regulation of iron homeostasis and related diseases. Mediat Inflamm 2020:6062094–6062011. https://doi.org/10.1155/2020/6062094

    Article  CAS  Google Scholar 

  10. Adam-Vizi V (2005) Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources. Antioxid Redox Signal 7(9-10):1140–1149. https://doi.org/10.1089/ars.2005.7.1140

    Article  CAS  PubMed  Google Scholar 

  11. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yang WS, Stockwell BR (2016) Ferroptosis: death by lipid peroxidation. Trends Cell Biol 26(3):165–176. https://doi.org/10.1016/j.tcb.2015.10.014

    Article  CAS  PubMed  Google Scholar 

  13. Magtanong L, Ko PJ, Dixon SJ (2016) Emerging roles for lipids in non-apoptotic cell death. Cell Death Differ 23(7):1099–1109. https://doi.org/10.1038/cdd.2016.25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hao S, Liang B, Huang Q, Dong S, Wu Z, He W, Shi M (2018) Metabolic networks in ferroptosis. Oncol Lett 15(4):5405–5411. https://doi.org/10.3892/ol.2018.8066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yang WS, Stockwell BR (2008) Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 15(3):234–245. https://doi.org/10.1016/j.chembiol.2008.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tang M, Chen Z, Wu D, Chen L (2018) Ferritinophagy/ferroptosis: iron-related newcomers in human diseases. J Cell Physiol 233(12):9179–9190. https://doi.org/10.1002/jcp.26954

    Article  CAS  PubMed  Google Scholar 

  17. Ashraf A, Jeandriens J, Parkes HG, So PW (2020) Iron dyshomeostasis, lipid peroxidation and perturbed expression of cystine/glutamate antiporter in Alzheimer’s disease: evidence of ferroptosis. Redox Biol 32:101494. https://doi.org/10.1016/j.redox.2020.101494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mahoney-Sanchez L, Bouchaoui H, Ayton S, Devos D, Duce JA, Devedjian JC (2020) Ferroptosis and its potential role in the physiopathology of Parkinson’s disease. Progr Neurobiol 101890. https://doi.org/10.1016/j.pneurobio.2020.101890

  19. Xu H, Wang Y, Song N, Wang J, Jiang H, Xie J (2017) New progress on the role of glia in iron metabolism and iron-induced degeneration of dopamine neurons in Parkinson’s disease. Front Mol Neurosci 10:455. https://doi.org/10.3389/fnmol.2017.00455

    Article  CAS  PubMed  Google Scholar 

  20. Shi H, Bencze KZ, Stemmler TL, Philpott CC (2008) A cytosolic iron chaperone that delivers iron to ferritin. Science 320(5880):1207–1210. https://doi.org/10.1126/science.1157643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Theil EC (1987) Ferritin: structure, gene regulation, and cellular function in animals, plants, and microorganisms. Annu Rev Biochem 56:289–315. https://doi.org/10.1146/annurev.bi.56.070187.001445

    Article  CAS  PubMed  Google Scholar 

  22. Arosio P, Ingrassia R, Cavadini P (2009) Ferritins: a family of molecules for iron storage, antioxidation and more. Biochim Biophys Acta 1790(7):589–599. https://doi.org/10.1016/j.bbagen.2008.09.004

    Article  CAS  PubMed  Google Scholar 

  23. Andrews SC, Robinson AK, Rodríguez-Quiñones F (2003) Bacterial iron homeostasis. FEMS Microbiol Rev 27(2-3):215–237. https://doi.org/10.1016/s0168-6445(03)00055-x

    Article  CAS  PubMed  Google Scholar 

  24. Macedo S, Romão CV, Mitchell E, Matias PM, Liu MY, Xavier AV, LeGall J, Teixeira M et al (2003) The nature of the di-iron site in the bacterioferritin from Desulfovibrio desulfuricans. Nat Struct Biol 10(4):285–290. https://doi.org/10.1038/nsb909

    Article  CAS  PubMed  Google Scholar 

  25. da Silva VK, de Freitas BS, Dornelles VC, Kist LW, Bogo MR, Silva MC, Streck EL, Hallak JE et al (2018) Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: reversal by cannabidiol. Brain Res Bull 139:1–8. https://doi.org/10.1016/j.brainresbull.2018.01.014

    Article  CAS  PubMed  Google Scholar 

  26. Finazzi D, Arosio P (2014) Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration. Arch Toxicol 88(10):1787–1802. https://doi.org/10.1007/s00204-014-1329-0

    Article  CAS  PubMed  Google Scholar 

  27. Andrews SC (2010) The Ferritin-like superfamily: evolution of the biological iron storeman from a rubrerythrin-like ancestor. Biochim Biophys Acta 1800(8):691–705. https://doi.org/10.1016/j.bbagen.2010.05.010

    Article  CAS  PubMed  Google Scholar 

  28. Zang J, Chen H, Zhao G, Wang F, Ren F (2017) Ferritin cage for encapsulation and delivery of bioactive nutrients: from structure, property to applications. Crit Rev Food Sci Nutr 57(17):3673–3683. https://doi.org/10.1080/10408398.2016.1149690

    Article  CAS  PubMed  Google Scholar 

  29. Theil EC (2013) Ferritin: the protein nanocage and iron biomineral in health and in disease. Inorg Chem 52(21):12223–12233. https://doi.org/10.1021/ic400484n

    Article  CAS  PubMed  Google Scholar 

  30. Naumova AV, Balu N, Yarnykh VL, Reinecke H, Murry CE, Yuan C (2014) Magnetic resonance imaging tracking of graft survival in the infarcted heart: iron oxide particles versus ferritin overexpression approach. J Cardiovasc Pharmacol Ther 19(4):358–367. https://doi.org/10.1177/1074248414525999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Laghaei R, Kowallis W, Evans DG, Coalson RD (2014) Calculation of iron transport through human H-chain ferritin. J Phys Chem A 118(35):7442–7453. https://doi.org/10.1021/jp500198u

    Article  CAS  PubMed  Google Scholar 

  32. Worwood M (1982) Ferritin in human tissues and serum. Clin Haematol 11(2):275–307

    CAS  PubMed  Google Scholar 

  33. Powell LW, Alpert E, Isselbacher KJ, Drysdale JW (1975) Human isoferritins: organ specific iron and apoferritin distribution. Br J Haematol 30(1):47–55. https://doi.org/10.1111/j.1365-2141.1975.tb00516.x

    Article  CAS  PubMed  Google Scholar 

  34. Hintze KJ, Theil EC (2006) Cellular regulation and molecular interactions of the ferritins. Cell Mol Life Sci 63(5):591–600. https://doi.org/10.1007/s00018-005-5285-y

    Article  CAS  PubMed  Google Scholar 

  35. Cowley JM, Janney DE, Gerkin RC, Buseck PR (2000) The structure of ferritin cores determined by electron nanodiffraction. J Struct Biol 131(3):210–216. https://doi.org/10.1006/jsbi.2000.4292

    Article  CAS  PubMed  Google Scholar 

  36. Koralewski M, Balejcikova L, Mitroova Z, Pochylski M, Baranowski M, Kopcansky P (2018) Morphology and magnetic structure of the ferritin core during iron loading and release by magnetooptical and NMR methods. ACS Appl Mater Interfaces 10(9):7777–7787. https://doi.org/10.1021/acsami.7b18304

    Article  CAS  PubMed  Google Scholar 

  37. Meyron-Holtz EG, Moshe-Belizowski S, Cohen LA (2011) A possible role for secreted ferritin in tissue iron distribution. J Neural Transm 118(3):337–347. https://doi.org/10.1007/s00702-011-0582-0

    Article  CAS  PubMed  Google Scholar 

  38. De Domenico I, Ward DM, Kaplan J (2010) Autophagy, ferritin and iron chelation. Autophagy 6(1):157–157. https://doi.org/10.4161/auto.6.1.10587

    Article  PubMed  Google Scholar 

  39. De Domenico I, Vaughn MB, Li LT, Bagley D, Musci G, Ward DM, Kaplan J (2006) Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome. EMBO J 25(22):5396–5404. https://doi.org/10.1038/sj.emboj.7601409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kuhn LC (2015) Iron regulatory proteins and their role in controlling iron metabolism. Metallomics 7(2):232–243. https://doi.org/10.1039/c4mt00164h

    Article  CAS  PubMed  Google Scholar 

  41. Haldar S, Bevers LE, Tosha T, Theil EC (2011) Moving iron through ferritin protein nanocages depends on residues throughout each four alpha-helix bundle subunit. J Biol Chem 286(29):25620–25627. https://doi.org/10.1074/jbc.M110.205278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Koorts AM, Viljoen M (2007) Ferritin and ferritin isoforms II: protection against uncontrolled cellular proliferation, oxidative damage and inflammatory processes. Arch Physiol Biochem 113(2):55–64. https://doi.org/10.1080/13813450701422575

    Article  CAS  PubMed  Google Scholar 

  43. Gilmore TD (2006) Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 25(51):6680–6684. https://doi.org/10.1038/sj.onc.1209954

    Article  CAS  PubMed  Google Scholar 

  44. Torti FM, Torti SV (2002) Regulation of ferritin genes and protein. Blood 99(10):3505–3516. https://doi.org/10.1182/blood.v99.10.3505

    Article  CAS  PubMed  Google Scholar 

  45. Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, Jayawardena S, De Smaele E et al (2004) Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell 119(4):529–542. https://doi.org/10.1016/j.cell.2004.10.017

    Article  CAS  PubMed  Google Scholar 

  46. Pietsch EC, Chan JY, Torti FM, Torti SV (2003) Nrf2 mediates the induction of ferritin H in response to xenobiotics and cancer chemopreventive dithiolethiones. J Biol Chem 278(4):2361–2369. https://doi.org/10.1074/jbc.M210664200

    Article  CAS  PubMed  Google Scholar 

  47. Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9(2):102–114. https://doi.org/10.1038/nrg2290

    Article  CAS  PubMed  Google Scholar 

  48. Pillai RS, Bhattacharyya SN, Filipowicz W (2007) Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol 17(3):118–126. https://doi.org/10.1016/j.tcb.2006.12.007

    Article  CAS  PubMed  Google Scholar 

  49. Shpyleva SI, Tryndyak VP, Kovalchuk O, Starlard-Davenport A, Chekhun VF, Beland FA, Pogribny IP (2011) Role of ferritin alterations in human breast cancer cells. Breast Cancer Res Treat 126(1):63–71. https://doi.org/10.1007/s10549-010-0849-4

    Article  CAS  PubMed  Google Scholar 

  50. Pulos-Holmes MC, Srole DN, Juarez MG, Lee ASY, McSwiggen DT, Ingolia NT, Cate JH (2019) Repression of ferritin light chain translation by human eIF3. Elife 8:ARTN e48193. https://doi.org/10.7554/eLife.48193

    Article  Google Scholar 

  51. Dowdle WE, Nyfeler B, Nagel J, Elling RA, Liu SM, Triantafellow E, Menon S, Wang ZC et al (2014) Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat Cell Biol 16(11):1069. https://doi.org/10.1038/ncb3053

    Article  CAS  PubMed  Google Scholar 

  52. Mancias JD, Wang XX, Gygi SP, Harper JW, Kimmelman AC (2014) Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509(7498):105. https://doi.org/10.1038/nature13148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Srivastava AK, Flint N, Kreckel H, Gryzik M, Poli M, Arosio P, Bou-Abdallah F (2020) Thermodynamic and kinetic studies of the interaction of nuclear receptor coactivator-4 (NCOA4) with human ferritin. Biochemistry 59(29):2707–2717. https://doi.org/10.1021/acs.biochem.0c00246

    Article  CAS  PubMed  Google Scholar 

  54. Gryzik M, Srivastava A, Longhi G, Bertuzzi M, Gianoncelli A, Carmona F, Poli M, Arosio P (2017) Expression and characterization of the ferritin binding domain of nuclear receptor coactivator-4 (NCOA4). Biochim Biophys Acta Gen Subj 1861(11 Pt A):2710–2716. https://doi.org/10.1016/j.bbagen.2017.07.015

    Article  CAS  PubMed  Google Scholar 

  55. Quiles Del Rey M, Mancias JD (2019) NCOA4-mediated ferritinophagy: a potential link to neurodegeneration. Front Neurosci 13:238. https://doi.org/10.3389/fnins.2019.00238

    Article  PubMed  PubMed Central  Google Scholar 

  56. Dong XP, Cheng XP, Mills E, Delling M, Wang FD, Kurz T, Xu HX (2008) The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455(7215):992–U978. https://doi.org/10.1038/nature07311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. La A, Nguyen T, Tran K, Sauble E, Tu D, Gonzalez A, Kidane TZ, Soriano C et al (2018) Mobilization of iron from ferritin: new steps and details. Metallomics 10(1):154–168. https://doi.org/10.1039/c7mt00284j

    Article  CAS  PubMed  Google Scholar 

  58. Goodwin JM, Dowdle WE, DeJesus R, Wang ZC, Bergman P, Kobylarz M, Lindeman A, Xavier RJ et al (2017) Autophagy-independent lysosomal targeting regulated by ULK1/2-FIP200 and ATG9. Cell Rep 20(10):2341–2356. https://doi.org/10.1016/j.celrep.2017.08.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Asano T, Komatsu M, Yamaguchi-Iwai Y, Ishikawa F, Mizushima N, Iwai K (2011) Distinct mechanisms of ferritin delivery to lysosomes in iron-depleted and iron-replete cells. Mol Cell Biol 31(10):2040–2052. https://doi.org/10.1128/Mcb.01437-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang YH, Mikhael M, Xu DX, Li YY, Shan SL, Ning B, Li W, Nie GJ et al (2010) Lysosomal proteolysis is the primary degradation pathway for cytosolic ferritin and cytosolic ferritin degradation is necessary for iron exit. Antioxid Redox Signal 13(7):999–1009. https://doi.org/10.1089/ars.2010.3129

    Article  CAS  PubMed  Google Scholar 

  61. Kurz T, Eaton JW, Brunk UT (2011) The role of lysosomes in iron metabolism and recycling. Int J Biochem Cell Biol 43(12):1686–1697. https://doi.org/10.1016/j.biocel.2011.08.016

    Article  CAS  PubMed  Google Scholar 

  62. Kurz T, Terman A, Gustafsson B, Brunk UT (2008) Lysosomes in iron metabolism, ageing and apoptosis. Histochem Cell Biol 129(4):389–406. https://doi.org/10.1007/s00418-008-0394-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rudeck M, Volk T, Sitte N, Grune T (2000) Ferritin oxidation in vitro: implication of iron release and degradation by the 20S proteasome. IUBMB Life 49(5):451–456

    Article  CAS  PubMed  Google Scholar 

  64. Clegg GA, Fitton JE, Harrison PM, Treffry A (1980) Ferritin: molecular structure and iron-storage mechanisms. Prog Biophys Mol Biol 36(2-3):56–86

    CAS  PubMed  Google Scholar 

  65. Tosha T, Behera RK, Theil EC (2012) Ferritin ion channel disorder inhibits Fe(II)/O-2 reactivity at distant sites. Inorg Chem 51(21):11406–11411. https://doi.org/10.1021/ic3010135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hasan MR, Tosha T, Theil EC (2008) Ferritin contains less iron (Fe-59) in cells when the protein pores are unfolded by mutation. J Biol Chem 283(46):31394–31400. https://doi.org/10.1074/jbc.M806025200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ferreira C, Bucchini D, Martin ME, Levi S, Arosio P, Grandchamp B, Beaumont C (2000) Early embryonic lethality of H ferritin gene deletion in mice. J Biol Chem 275(5):3021–3024. https://doi.org/10.1074/jbc.275.5.3021

    Article  CAS  PubMed  Google Scholar 

  68. Zolea F, Biamonte F, Candeloro P, Di Sanzo M, Cozzi A, Di Vito A, Quaresima B, Lobello N et al (2015) H ferritin silencing induces protein misfolding in K562 cells: a Raman analysis. Free Radic Biol Med 89:614–623. https://doi.org/10.1016/j.freeradbiomed.2015.07.161

    Article  CAS  PubMed  Google Scholar 

  69. Li W, Garringer HJ, Goodwin CB, Richine B, Acton A, VanDuyn N, Muhoberac BB, Irimia-Dominguez J et al (2015) Systemic and cerebral iron homeostasis in ferritin knock-out mice. PLoS One 10(1):ARTN e0117435. https://doi.org/10.1371/journal.pone.0117435

    Article  CAS  Google Scholar 

  70. Antosiewicz J, Ziolkowski W, Kaczor JJ, Herman-Antosiewicz A (2007) Tumor necrosis factor-alpha-induced reactive oxygen species formation is mediated by JNK1-dependent ferritin degradation and elevation of labile iron pool. Free Radic Biol Med 43(2):265–270. https://doi.org/10.1016/j.freeradbiomed.2007.04.023

    Article  CAS  PubMed  Google Scholar 

  71. Moreira AC, Mesquita G, Gomes MS (2020) Ferritin: an inflammatory player keeping iron at the core of pathogen-host interactions. Microorganisms 8(4):ARTN 589. https://doi.org/10.3390/microorganisms8040589

    Article  CAS  Google Scholar 

  72. Slaats J, ten Oever J, van de Veerdonk FL, Netea MG (2016) IL-1 beta/IL-6/CRP and IL-18/ferritin: distinct inflammatory programs in infections. PLoS Pathog 12(12):ARTN e1005973. https://doi.org/10.1371/journal.ppat.1005973

    Article  CAS  Google Scholar 

  73. Festa L, Gutoskey CJ, Graziano A, Waterhouse BD, Meucci O (2015) Induction of interleukin-1 beta by human immunodeficiency virus-1 viral proteins leads to increased levels of neuronal ferritin heavy chain, synaptic injury, and deficits in flexible attention. J Neurosci 35(29):10550–10561. https://doi.org/10.1523/Jneurosci.4403-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Recalcati S, Invernizzi P, Arosio P, Cairo G (2008) New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity. J Autoimmun 30(1-2):84–89. https://doi.org/10.1016/j.jaut.2007.11.003

    Article  CAS  PubMed  Google Scholar 

  75. Cohen LA, Gutierrez L, Weiss A, Leichtmann-Bardoogo Y, Zhang DL, Crooks DR, Sougrat R, Morgenstern A et al (2010) Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 116(9):1574–1584. https://doi.org/10.1182/blood-2009-11-253815

    Article  CAS  PubMed  Google Scholar 

  76. Kimura T, Jia JY, Kumar S, Choi SW, Gu YX, Mudd M, Dupont N, Jiang SY et al (2017) Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy. EMBO J 36(1):42–60. https://doi.org/10.15252/embj.201695081

    Article  CAS  PubMed  Google Scholar 

  77. Takats S, Nagy P, Varga A, Pircs K, Karpati M, Varga K, Kovacs AL, Hegedus K et al (2013) Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila. FEBS J 280:269–269

    Google Scholar 

  78. Truman-Rosentsvit M, Berenbaum D, Spektor L, Cohen LA, Belizowsky-Moshe S, Lifshitz L, Ma J, Li W et al (2018) Ferritin is secreted via 2 distinct nonclassical vesicular pathways. Blood 131(3):342–352. https://doi.org/10.1182/blood-2017-02-768580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hulet SW, Hess EJ, Debinski W, Arosio P, Bruce K, Powers S, Connor JR (1999) Characterization and distribution of ferritin binding sites in the adult mouse brain. J Neurochem 72(2):868–874. https://doi.org/10.1046/j.1471-4159.1999.720868.x

    Article  CAS  PubMed  Google Scholar 

  80. Chiou B, Neely EB, Mcdevitt DS, Simpson IA, Connor JR (2020) Transferrin and H-ferritin involvement in brain iron acquisition during postnatal development: impact of sex and genotype. J Neurochem 152(3):381–396. https://doi.org/10.1111/jnc.14834

    Article  CAS  PubMed  Google Scholar 

  81. Fisher J, Devraj K, Ingram J, Slagle-Webb B, Madhankumar AB, Liu X, Klinger M, Simpson IA et al (2007) Ferritin: a novel mechanism for delivery of iron to the brain and other organs. Am J Physiol Cell Physiol 293(2):C641–C649. https://doi.org/10.1152/ajpcell.00599.2006

    Article  CAS  PubMed  Google Scholar 

  82. Chen TT, Li L, Chung DH, Allen CDC, Torti SV, Torti FM, Cyster JG, Chen CY et al (2005) TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J Exp Med 202(7):955–965. https://doi.org/10.1084/jem.20042433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Todorich B, Zhang XS, Slagle-Webb B, Seaman WE, Connor JR (2008) Tim-2 is the receptor for H-ferritin on oligodendrocytes. J Neurochem 107(6):1495–1505. https://doi.org/10.1111/j.1471-4159.2008.05678.x

    Article  CAS  PubMed  Google Scholar 

  84. Chiou B, Lucassen E, Sather M, Kallianpur A, Connor J (2018) Semaphorin4A and H-ferritin utilize Tim-1 on human oligodendrocytes: a novel neuro-immune axis. Glia 66(7):1317–1330. https://doi.org/10.1002/glia.23313

    Article  PubMed  PubMed Central  Google Scholar 

  85. Sakamoto S, Kawabata H, Masuda T, Uchiyama T, Mizumoto C, Ohmori K, Koeffler HP, Kadowaki N et al (2015) H-Ferritin is preferentially incorporated by human erythroid cells through transferrin receptor 1 in a threshold-dependent manner. PLoS One 10(10):ARTN e0139915. https://doi.org/10.1371/journal.pone.0139915

    Article  CAS  Google Scholar 

  86. Li L, Fang CJ, Ryan JC, Niemi EC, Lebron JA, Bjorkman PJ, Arase H, Torti FM et al (2010) Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc Natl Acad Sci U S A 107(8):3505–3510. https://doi.org/10.1073/pnas.0913192107

    Article  PubMed  PubMed Central  Google Scholar 

  87. Li JY, Paragas N, Ned RM, Qiu AD, Viltard M, Leete T, Drexler IR, Chen X et al (2009) Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Dev Cell 16(1):35–46. https://doi.org/10.1016/j.devcel.2008.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Greco TM, Seeholzer SH, Mak A, Spruce L, Ischiropoulos H (2010) Quantitative mass spectrometry-based proteomics reveals the dynamic range of primary mouse astrocyte protein secretion. J Proteome Res 9(5):2764–2774. https://doi.org/10.1021/pr100134n

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Schonberg DL, Goldstein EZ, Sahinkaya FR, Wei P, Popovich PG, McTigue DM (2012) Ferritin stimulates oligodendrocyte genesis in the adult spinal cord and can be transferred from macrophages to NG2 cells in vivo. J Neurosci 32(16):5374–5384. https://doi.org/10.1523/Jneurosci.3517-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Li Y, Guan Q, Chen Y, Han H, Liu W, Nie Z (2013) Transferrin receptor and ferritin-H are developmentally regulated in oligodendrocyte lineage cells. Neural Regen Res 8(1):6–12. https://doi.org/10.3969/j.issn.1673-5374.2013.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mukherjee C, Kling T, Russo B, Miebach K, Kess E, Schifferer M, Pedro LD, Weikert U et al (2020) Oligodendrocytes provide antioxidant defense function for neurons by secreting ferritin heavy chain. Cell Metab 32(2):259–272 e210. https://doi.org/10.1016/j.cmet.2020.05.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gotz ME, Double K, Gerlach M, Youdim MBH, Riederer P (2004) The relevance of iron in the pathogenesis of Parkinson’s disease. Ann N Y Acad Sci 1012:193–208. https://doi.org/10.1196/annals.1306.017

    Article  CAS  PubMed  Google Scholar 

  93. Friedman A, Galazka-Friedman J (2012) The history of the research of iron in parkinsonian substantia nigra. J Neural Transm 119(12):1507–1510. https://doi.org/10.1007/s00702-012-0894-8

    Article  CAS  PubMed  Google Scholar 

  94. Quintana C, Gutierrez L (2010) Could a dysfunction of ferritin be a determinant factor in the aetiology of some neurodegenerative diseases? BBA-Gen Subjects 1800(8):770–782. https://doi.org/10.1016/j.bbagen.2010.04.012

    Article  CAS  Google Scholar 

  95. Kuiper MA, Mulder C, van Kamp GJ, Scheltens P, Wolters EC (1994) Cerebrospinal fluid ferritin levels of patients with Parkinson’s disease, Alzheimer’s disease, and multiple system atrophy. J Neural Transm Park Dis Dement Sect 7(2):109–114. https://doi.org/10.1007/BF02260965

    Article  CAS  PubMed  Google Scholar 

  96. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909. https://doi.org/10.1016/s0896-6273(03)00568-3

    Article  CAS  PubMed  Google Scholar 

  97. Kansara S, Trivedi A, Chen S, Jankovic J, Le WD (2013) Early diagnosis and therapy of Parkinson’s disease: can disease progression be curbed? J Neural Transm 120(1):197–210. https://doi.org/10.1007/s00702-012-0840-9

    Article  CAS  PubMed  Google Scholar 

  98. Cui J, Guo X, Li Q, Song N, Xie J (2020) Hepcidin-to-ferritin ratio is decreased in astrocytes with extracellular alpha-synuclein and iron exposure. Front Cell Neurosci 14:47. https://doi.org/10.3389/fncel.2020.00047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Rhodes SL, Ritz B (2008) Genetics of iron regulation and the possible role of iron in Parkinson’s disease. Neurobiol Dis 32(2):183–195. https://doi.org/10.1016/j.nbd.2008.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Jiang H, Wang J, Rogers J, Xie JX (2017) Brain iron metabolism dysfunction in Parkinson’s disease. Mol Neurobiol 54(4):3078–3101. https://doi.org/10.1007/s12035-016-9879-1

    Article  CAS  PubMed  Google Scholar 

  101. Yu XJ, Du TT, Song N, He Q, Shen Y, Jiang H, Xie JX (2013) Decreased iron levels in the temporal cortex in postmortem human brains with Parkinson disease. Neurology 80(5):492–495. https://doi.org/10.1212/WNL.0b013e31827f0ebb

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Xu HM, Jiang H, Wang J, Luo B, Xie JX (2008) Over-expressed human divalent metal transporter 1 is involved in iron accumulation in MES23.5 cells. Neurochem Int 52(6):1044–1051. https://doi.org/10.1016/j.neuint.2007.10.019

    Article  CAS  PubMed  Google Scholar 

  103. Jiang H, Song N, Xu H, Zhang S, Wang J, Xie J (2010) Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell Res 20(3):345–356. https://doi.org/10.1038/cr.2010.20

    Article  CAS  PubMed  Google Scholar 

  104. Maharaj DS, Maharaj H, Daya S, Glass BD (2006) Melatonin and 6-hydroxymelatonin protect against iron-induced neurotoxicity. J Neurochem 96(1):78–81. https://doi.org/10.1111/j.1471-4159.2005.03532.x

    Article  CAS  PubMed  Google Scholar 

  105. Hou W, Xie YC, Song XX, Sun XF, Lotze MT, Zeh HJ, Kang R, Tang DL (2016) Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12(8):1425–1428. https://doi.org/10.1080/15548627.2016.1187366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gerlach M, Riederer P, Double KL (2008) Neuromelanin-bound ferric iron as an experimental model of dopaminergic neurodegeneration in Parkinson’s disease. Parkinsonism Relat Disord 14(Suppl 2):S185–S188. https://doi.org/10.1016/j.parkreldis.2008.04.028

    Article  PubMed  Google Scholar 

  107. Shamoto-Nagai M, Maruyama W, Yi H, Akao Y, Tribl F, Gerlach M, Osawa T, Riederer P et al (2006) Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26S proteasome. J Neural Transm 113(5):633–644. https://doi.org/10.1007/s00702-005-0410-5

    Article  CAS  PubMed  Google Scholar 

  108. Dexter DT, Jenner P, Schapira AH, Marsden CD (1992) Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson’s Disease Research Group. Ann Neurol 32(Suppl):S94–S100. https://doi.org/10.1002/ana.410320716

    Article  CAS  PubMed  Google Scholar 

  109. Kaur D, Rajagopalan S, Andersen JK (2009) Chronic expression of H-ferritin in dopaminergic midbrain neurons results in an age-related expansion of the labile iron pool and subsequent neurodegeneration: implications for Parkinson’s disease. Brain Res 1297:17–22. https://doi.org/10.1016/j.brainres.2009.08.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Levi S, Corsi B, Bosisio M, Invernizzi R, Volz A, Sanford D, Arosio P, Drysdale J (2001) A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem 276(27):24437–24440. https://doi.org/10.1074/jbc.C100141200

    Article  CAS  PubMed  Google Scholar 

  111. Gao G, Chang YZ (2014) Mitochondrial ferritin in the regulation of brain iron homeostasis and neurodegenerative diseases. Front Pharmacol 5:19. https://doi.org/10.3389/fphar.2014.00019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Shi ZH, Nie G, Duan XL, Rouault T, Wu WS, Ning B, Zhang N, Chang YZ et al (2010) Neuroprotective mechanism of mitochondrial ferritin on 6-hydroxydopamine-induced dopaminergic cell damage: implication for neuroprotection in Parkinson’s disease. Antioxid Redox Signal 13(6):783–796. https://doi.org/10.1089/ars.2009.3018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Guan H, Yang H, Yang M, Yanagisawa D, Bellier JP, Mori M, Takahata S, Nonaka T et al (2017) Mitochondrial ferritin protects SH-SY5Y cells against H2O2-induced oxidative stress and modulates alpha-synuclein expression. Exp Neurol 291:51–61. https://doi.org/10.1016/j.expneurol.2017.02.001

    Article  CAS  PubMed  Google Scholar 

  114. Rijal Upadhaya A, Kosterin I, Kumar S, von Arnim CA, Yamaguchi H, Fandrich M, Walter J, Thal DR (2014) Biochemical stages of amyloid-beta peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer’s disease. Brain J Neurol 137(Pt 3):887–903. https://doi.org/10.1093/brain/awt362

    Article  Google Scholar 

  115. Hanseeuw BJ, Lopera F, Sperling RA, Norton DJ, Guzman-Velez E, Baena A, Pardilla-Delgado E, Schultz AP et al (2019) Striatal amyloid is associated with tauopathy and memory decline in familial Alzheimer’s disease. Alzheimers Res Ther 11(1):17. https://doi.org/10.1186/s13195-019-0468-1

    Article  PubMed  PubMed Central  Google Scholar 

  116. Bulk M, van der Weerd L, Breimer W, Lebedev N, Webb A, Goeman JJ, Ward RJ, Huber M et al (2018) Quantitative comparison of different iron forms in the temporal cortex of Alzheimer patients and control subjects. Sci Rep 8(1):6898. https://doi.org/10.1038/s41598-018-25021-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Everett J, Collingwood JF, Tjendana-Tjhin V, Brooks J, Lermyte F, Plascencia-Villa G, Hands-Portman I, Dobson J et al (2018) Nanoscale synchrotron X-ray speciation of iron and calcium compounds in amyloid plaque cores from Alzheimer’s disease subjects. Nanoscale 10(25):11782–11796. https://doi.org/10.1039/c7nr06794a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Liu B, Moloney A, Meehan S, Morris K, Thomas SE, Serpell LC, Hider R, Marciniak SJ et al (2011) Iron promotes the toxicity of amyloid beta peptide by impeding its ordered aggregation. J Biol Chem 286(6):4248–4256. https://doi.org/10.1074/jbc.M110.158980

    Article  CAS  PubMed  Google Scholar 

  119. Egana JT, Zambrano C, Nunez MT, Gonzalez-Billault C, Maccioni RB (2003) Iron-induced oxidative stress modify tau phosphorylation patterns in hippocampal cell cultures. Biometals 16(1):215–223. https://doi.org/10.1023/a:1020727218493

    Article  CAS  PubMed  Google Scholar 

  120. Grunblatt E, Bartl J, Riederer P (2011) The link between iron, metabolic syndrome, and Alzheimer’s disease. J Neural Transm 118(3):371–379. https://doi.org/10.1007/s00702-010-0426-3

    Article  CAS  PubMed  Google Scholar 

  121. Fernandez T, Martinez-Serrano A, Cusso L, Desco M, Ramos-Gomez M (2018) Functionalization and characterization of magnetic nanoparticles for the detection of ferritin accumulation in Alzheimer’s disease. ACS Chem Neurosci 9(5):912–924. https://doi.org/10.1021/acschemneuro.7b00260

    Article  CAS  PubMed  Google Scholar 

  122. Quintana C, Lancin M, Marhic C, Perez M, Martin-Benito J, Avila J, Carrascosa JL (2000) Initial studies with high resolution TEM and electron energy loss spectroscopy studies of ferritin cores extracted from brains of patients with progressive supranuclear palsy and Alzheimer disease. Cell Mol Biol (Noisy-le-Grand) 46(4):807–820

    CAS  Google Scholar 

  123. Wang L, Yang H, Zhao S, Sato H, Konishi Y, Beach TG, Abdelalim EM, Bisem NJ et al (2011) Expression and localization of mitochondrial ferritin mRNA in Alzheimer’s disease cerebral cortex. PLoS One 6(7):e22325. https://doi.org/10.1371/journal.pone.0022325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wu WS, Zhao YS, Shi ZH, Chang SY, Nie GJ, Duan XL, Zhao SM, Wu Q et al (2013) Mitochondrial ferritin attenuates beta-amyloid-induced neurotoxicity: reduction in oxidative damage through the Erk/P38 mitogen-activated protein kinase pathways. Antioxid Redox Signal 18(2):158–169. https://doi.org/10.1089/ars.2011.4285

    Article  CAS  PubMed  Google Scholar 

  125. Yang H, Guan H, Yang M, Liu Z, Takeuchi S, Yanagisawa D, Vincent SR, Zhao S et al (2015) Upregulation of mitochondrial ferritin by proinflammatory cytokines: implications for a role in Alzheimer’s disease. J Alzheimers Dis 45(3):797–811. https://doi.org/10.3233/JAD-142595

    Article  CAS  PubMed  Google Scholar 

  126. Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ et al (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28(4):350–354. https://doi.org/10.1038/ng571

    Article  CAS  PubMed  Google Scholar 

  127. Cozzi A, Orellana DI, Santambrogio P, Rubio A, Cancellieri C, Giannelli S, Ripamonti M, Taverna S et al (2019) Stem cell modeling of neuroferritinopathy reveals iron as a determinant of senescence and ferroptosis during neuronal aging. Stem Cell Rep 13(5):832–846. https://doi.org/10.1016/j.stemcr.2019.09.002

    Article  CAS  Google Scholar 

  128. Cassidy AJ, Williams ER, Goldsmith P, Baker SN, Baker MR (2011) The man who could not walk backward: an unusual presentation of neuroferritinopathy. Mov Disord 26(2):362–364. https://doi.org/10.1002/mds.23415

    Article  PubMed  PubMed Central  Google Scholar 

  129. Levi S, Rovida E (2015) Neuroferritinopathy: from ferritin structure modification to pathogenetic mechanism. Neurobiol Dis 81:134–143. https://doi.org/10.1016/j.nbd.2015.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kumar N, Rizek P, Jog M (2016) Neuroferritinopathy: pathophysiology, presentation, differential diagnoses and management. Tremor Other Hyperkinet Mov (N Y) 6:355. https://doi.org/10.7916/D8KK9BHF

    Article  Google Scholar 

  131. Ni W, Li HF, Zheng YC, Wu ZY (2016) Ftl mutation in a Chinese pedigree with neuroferritinopathy. Neurol-Genet 2(3):UNSP e74. https://doi.org/10.1212/NXG.0000000000000074

    Article  Google Scholar 

  132. Vidal R, Ghetti B, Takao M, Brefel-Courbon C, Uro-Coste E, Glazier BS, Siani V, Benson MD et al (2004) Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene. J Neuropathol Exp Neurol 63(4):363–380. https://doi.org/10.1093/jnen/63.4.363

    Article  CAS  PubMed  Google Scholar 

  133. Schroder JM (2005) Ferritinopathy: diagnosis by muscle or nerve biopsy, with a note on other nuclear inclusion body diseases. Acta Neuropathol 109(1):109–114. https://doi.org/10.1007/s00401-004-0949-5

    Article  PubMed  Google Scholar 

  134. Mancuso M, Davidzon G, Kurlan RM, Tawil R, Bonilla E, Di Mauro S, Powers JM (2005) Hereditary ferritinopathy: a novel mutation, its cellular pathology, and pathogenetic insights. J Neuropathol Exp Neurol 64(4):280–294. https://doi.org/10.1093/jnen/64.4.280

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by grants from the National Foundation of Natural Science of China (31871202, 31771124), the Department of Science and Technology of Shandong Province (ZR2019MC057), Excellent Innovative Team of Shandong Province (2020KJK007), and Taishan Scholars Construction Project, Shandong.

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  1. Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, School of Basic Medicine, Qingdao University, Qingdao, 266071, China

    Na Zhang, Xiaoqi Yu, Junxia Xie & Huamin Xu

  2. Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China

    Na Zhang, Xiaoqi Yu, Junxia Xie & Huamin Xu

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  1. Na Zhang
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  2. Xiaoqi Yu
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HX conceived the original idea and designed the outlines of the study. NZ and XY conducted the literature review and prepared the figures for the manuscript. NZ wrote the manuscript. JX contributed to the editing of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Junxia Xie or Huamin Xu.

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Zhang, N., Yu, X., Xie, J. et al. New Insights into the Role of Ferritin in Iron Homeostasis and Neurodegenerative Diseases. Mol Neurobiol 58, 2812–2823 (2021). https://doi.org/10.1007/s12035-020-02277-7

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Keywords

  • Ferritin
  • Iron
  • Parkinson’s disease
  • Alzheimer’s disease
  • Neuroferritinopathy