Causes of accumulation of excess iron in the structures of the substantia nigra of the brain in Parkinson’s disease
https://doi.org/10.29413/ABS.2025-10.1.17
Abstract
A critical analysis of the literature on the factors contributing to the excessive accumulation of iron in the structures of the substantia nigra of the brain in Parkinson’s disease is presented. This morphological feature, along with such signs as the accumulation of an abnormal form of presynaptic protein alpha-synuclein in dopamine neurons, their rapid death and gliosis in the substantia nigra of the brain, is one of the most important in the pathomorphological picture of the disease.
It is shown that the excess of iron in the substantia nigra may be due to the influence of such factors as the effects of toxic metals (aluminum, mercury and lead) on the brain, impaired permeability of the blood-brain barrier, changes in the expression of metal-containing proteins and genetic mutations. At the same time, the role of factors such as the consumption of large amounts of iron with food and dietary supplements, and mitochondrial dysfunction in the formation of this morphological sign of Parkinson’s disease remains not fully understood.
Continuation of the study of the causes of accumulation of excess iron in the structures of the midbrain in Parkinson's disease and those consequences that may be caused by excessive accumulation of iron in these structures remain relevant for modern neurology.
The literature search was conducted in the databases PubMed and eLibrary.
About the Author
V. N. Salkov
Research Center of Neurology
Russian Federation
Russian Federation
Vladimir N. Salkov – Dr. Sc. (Med.), Senior Research Officer at the Laboratory of Neuromorphology, Brain Institute,
Volokolamskoye Highway 80, Moscow 125367
References
1. Hayes MT. Parkinson’s disease and parkinsonism. Am J Med. 2019; 132(7): 802-807. doi: 10.1016/j.amjmed.2019.03.001
2. Sveinbjornsdottir S. The clinical symptoms of Parkinson’s disease. J Neurochem. 2016; 139(1): 318-324. doi: 10.1111/jnc.13691
3. Skou LD, Johansen SK, Okarmus J, Meyer M. Pathogenesis of DJ-1/PARK7-mediated Parkinson’s disease. Cells. 2024; 13(4): 296. doi: 10.3390/cells13040296
4. Thomas GEC, Zarkali A, Ryten M, Shmueli K, Gil-Martinez AL, Leyland LA, et al. Regional brain iron and gene expression provide insights into neurodegeneration in Parkinson’s disease. Brain. 2021; 144(6): 1787-1798. doi: 10.1093/brain/awab084
5. Hare DJ, Double KL. Iron and dopamine: A toxic couple. Brain. 2016; 139: 1026-1035. doi: 10.1093/brain/aww022
6. Zeng W, Cai J, Zhang L, Peng Q. Iron deposition in Parkinson’s disease: A mini-review. Cell Mol Neurobiol. 2024; 44(1): 26. doi: 10.1007/s10571-024-01459-4
7. Knörle R. Neuromelanin in Parkinson’s disease: From Fenton reaction to calcium signaling. Neurotox Res. 2018; 33(2): 515-522. doi: 10.1007/s12640-017-9804-z
8. David S, Jhelum P, Ryan F, Jeong SY, Kroner A. Dysregulation of iron homeostasis in the central nervous system and the role of ferroptosis in neurodegenerative disorders. Antioxid Redox Signal. 2022; 37: 150-170. doi: 10.1089/ars.2021.0218
9. Roe K. An alternative explanation for Alzheimer’s disease and Parkinson’s disease initiation from specific antibiotics, gut microbiota dysbiosis and neurotoxins. Neurochem Res. 2022; 47(3): 517-530. doi: 10.1007/s11064-021-03467-y
10. Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol. 2005; 57(2): 176-179. doi: 10.1002/ana.20369
11. Ward RJ, 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. doi: 10.1016/s1474-4422(14)70117-6
12. Guerreiro RJ, Bras JM, Santana I, Januario C, Santiago B, Morgadinho AS, et al. Association of HFE common mutations with Parkinson’s disease, Alzheimer’s disease and mild cognitive impairment in a Portuguese cohort. BMC Neurol. 2006; 6: 24. doi: 10.1186/1471-2377-6-24
13. Li Y, Jiao Q, Xu H, Du X, Shi L, Jia F, et al. Biometal dyshomeostasis and toxic metal accumulations in the development of Alzheimer’s disease. Front Mol Neurosci. 2017; 10: 339. doi: 10.3389/fnmol.2017.00339
14. Foley PB, Hare DJ, Double KL. A brief history of brain iron accumulation in Parkinson disease and related disorders. J Neural Transm (Vienna). 2022; 129(5-6): 505-520. doi: 10.1007/s00702-022-02505-5
15. Zecca L, Pietra R, Goj C, Mecacci C, Radice D, Sabbioni E. Iron and other metals in neuromelanin, substantia nigra, and putamen of human brain. J Neurochem. 1994; 62(3): 1097-1101. doi: 10.1046/j.1471-4159.1994.62031097.x
16. Biesemeier A, Eibl O, Eswara S, Audinot JN, Wirtz T, Pezzoli G, et al. Elemental mapping of neuromelanin organelles of human substantia nigra: Correlative ultrastructural and chemical analysis by analytical transmission electron microscopy and nanosecondary ion mass spectrometry. J Neurochem. 2016; 138(2): 339-353. doi: 10.1111/jnc.13648
17. Igbokwe IO, Igwenagu E, Igbokwe NA. Aluminium toxicosis: A review of toxic actions and effects. Interdiscip Toxicol. 2019; 12(2): 45-70. doi: 10.2478/intox-2019-0007
18. Pamphlett R, Bishop DP. The toxic metal hypothesis for neurological disorders. Front Neurol. 2023; 14: 1173779. doi: 10.3389/fneur.2023.1173779
19. Schäffer E, Piel J. Das Exposom im Fokus prlventiver Maznahmen für die Alzheimer- und Parkinson-Erkrankung [The exposome in the context of preventive measures for Alzheimer’s and Parkinson’s diseases]. Nervenarzt. 2023; 94(10): 892-903. (In German). doi: 10.1007/s00115-023-01538-9
20. Gunnarsson LG, Bodin L. Occupational exposures and neurodegenerative diseases – A systematic literature review and meta-analyses. Int J Environ Res Public Health. 2019; 16(3): 337. doi: 10.3390/ijerph16030337
21. Garza-Lombу C, Posadas Y, Quintanar L, Gonsebatt ME, Franco R. Neurotoxicity linked to dysfunctional metal ion homeostasis and xenobiotic metal exposure: Redox signaling and oxidative stress. Antioxid Redox Signal. 2018; 28(18): 1669-1703. doi: 10.1089/ars.2017.7272
22. Mezzaroba L, Alfieri DF, Colado Simão AN, Vissoci Reiche EM. The role of zinc, copper, manganese and iron in neurodegenerative diseases. Neurotoxicology. 2019; 74: 230-241. doi: 10.1016/j.neuro.2019.07.007
23. Schofield K. The metal neurotoxins: An important role in current human neural epidemics? Int J Environ Res Public Health. 2017; 14(12): 1511. doi: 10.3390/ijerph14121511
24. Baj J, Flieger W, Barbachowska A, Kowalska B, Flieger M, Forma A, et al. Consequences of disturbing manganese homeostasis. Int J Mol Sci. 2023; 24(19): 14959. doi: 10.3390/ijms241914959
25. Gуrska A, Markiewicz-Gospodarek A, Markiewicz R, Chilimoniuk Z, Borowski B, Trubalski M, et al. Distribution of iron, copper, zinc and cadmium in glia, their influence on glial cells and relationship with neurodegenerative diseases. Brain Sci. 2023; 13(6): 911. doi: 10.3390/brainsci13060911
26. Bakulski KM, Seo YA, Hickman RC, Brandt D, Vadari HS, Hu H, et al. Heavy metals exposure and Alzheimer’s disease and related dementias. J Alzheimers Dis. 2020; 76(4): 1215-1242. doi: 10.3233/JAD-200282
27. Hémadi M, Miquel G, Kahn PH, El Hage Chahine JM. Aluminum exchange between citrate and human serum transferrin and interaction with transferrin receptor 1. Biochemistry. 2003; 42(10): 3120-3130. doi: 10.1021/bi020627p
28. Guo M, Ji X, Liu J. Hypoxia and alpha-synuclein: Inextricable link underlying the pathologic progression of Parkinson’s disease. Front Aging Neurosci. 2022; 14: 919343. doi: 10.3389/fnagi.2022.919343
29. Carboni E, Lingor P. Insights on the interaction of alphasynuclein and metals in the pathophysiology of Parkinson’s disease. Metallomics. 2015; 7: 395-404. doi: 10.1039/c4mt00339j
30. Bartels AL, Willemsen AT, Kortekaas R, de Jong BM, de Vries R, de Klerk O, et al. Decreased blood-brain barrier Pglycoprotein function in the progression of Parkinson’s disease, PSP and MSA. J Neural Transm (Vienna). 2008; 115(7): 1001-1009. doi: 10.1007/s00702-008-0030-y
31. Benarroch EE. The locus ceruleus norepinephrine system: Functional organization and potential clinical significance. Neurology. 2009; 73(20): 1699-1704. doi: 10.1212/WNL.0b013e3181c2937c
32. Yuan Y, Sun J, Dong Q, Cui M. Blood-brain barrier endothelial cells in neurodegenerative diseases: signals from the “barrier”. Front Neurosci. 2023; 17: 1047778. doi: 10.3389/fnins.2023.1047778
33. Baksi S, Tripathi AK, Singh N. Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrinbound iron: Implications for visual manifestations of Parkinson’s disease. Free Radic Biol Med. 2016; 97: 292-306. doi: 10.1016/j.freeradbiomed.2016.06.025
34. Trist BG, Hare DJ, Double KL. Oxidative stress in the aging substantia nigra and the etiology of Parkinson’s disease. Aging Cell. 2019; 18(6). 00:e13031. doi: 10.1111/acel.13031
35. Wang J, Bi M, Liu H, Song N, Xie J. The protective effect of lactoferrin on ventral mesencephalon neurons against MPP+ is not connected with its iron binding ability. Sci Rep. 2015; 5: 10729. doi: 10.1038/srep10729
36. Koziorowski D, Friedman A, Arosio P, Santambrogio P, Dziewulska D. ELISA reveals a difference in the structure of substantia nigra ferritin in Parkinson’s disease and incidental Lewy body compared to control. Parkinsonism Relat Disord. 2007; 13(4): 214–218. doi: 10.1016/j.parkreldis.2006.10.002
37. James SA, Roberts BR, Hare DJ, de Jonge MD, Birchall IE, Jenkins NL, et al. Direct in vivo imaging of ferrous iron dyshomeostasis in ageing Caenorhabditis elegans. Chem Sci. 2015; 6(5): 2952-2962. doi: 10.1039/c5sc00233h
38. Salazar J, Mena N, Hunot S, Prigent A, Alvarez-Fischer D, Arredondo M, et al. Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease. Proc Natl Acad Sci U S A. 2008; 105(47): 18578-18583. doi: 10.1073/pnas.0804373105
39. Hirsch EC. Iron transport in Parkinson’s disease. Parkinsonism Relat Disord. 2009; 15(3): 209-211. doi: 10.1016/S1353-8020(09)70816-8
40. Hare D, Ayton S, Bush A, Lei P. A delicate balance: Iron metabolism and diseases of the brain. Front Aging Neurosci. 2013; 5: 34. doi: 10.3389/fnagi.2013.00034
41. Sian-Hulsmann J, Riederer P. The role of alpha-synuclein as ferrireductase in neurodegeneration associated with Parkinson’s disease. J Neural Transm (Vienna). 2020; 127(5): 749-754. doi: 10.1007/s00702-020-02192-0
42. Abdeen AH, Trist BG, Double KL. Empirical evidence for biometal dysregulation in Parkinson’s disease from a systematic review and Bradford Hill analysis. NPJ Parkinsons Dis. 2022; 8(1): 83. doi: 10.1038/s41531-022-00345-4
43. Ayton S, Lei P, Hare DJ, Duce JA, George JL, Adlard PA, 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. doi: 10.1523/JNEUROSCI.3439-14.2015
44. Wong BX, Tsatsanis A, Lim LQ, Adlard PA, Bush AI, Duce JA. β-Amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin. PLoS One. 2014; 9(12): e114174. doi: 10.1371/journal.pone.0114174
45. Wang W, Zhang X, Gao Q, Xu H. TRPML1: An ion channel in the lysosome. Handb Exp Pharmacol. 2014; 222: 631-645. doi: 10.1007/978-3-642-54215-2_24
46. Mills E, Dong XP, Wang F, Xu H. Mechanisms of brain iron transport: Insight into neurodegeneration and CNS disorders. Future Med Chem. 2010; 2(1): 51-64. doi: 10.4155/fmc.09.140
47. Fonseca Ó, Ramos AS, Gomes LTS, Gomes MS, Moreira AC. New perspectives on circulating ferritin: Its role in health and disease. Molecules. 2023; 28(23): 7707. doi: 10.3390/molecules28237707
48. Kawabata H. The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis. Int J Hematol. 2018; 107(1): 31-43. doi: 10.1007/s12185-017-2365-3
49. Rhodes SL, Buchanan DD, Ahmed I, Taylor KD, Loriot MA, Sinsheimer JS, et al. Pooled analysis of iron-related genes in Parkinson’s disease: Association with transferrin. Neurobiol Dis. 2014; 62: 172-178. doi: 10.1016/j.nbd.2013.09.019
50. Mastroberardino PG, Hoffman EK, Horowitz MP, Betarbet R, Taylor G, Cheng D, et al. A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson’s disease. Neurobiol Dis. 2009; 34(3): 417-431. doi: 10.1016/j.nbd.2009.02.009
51. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H. Parkinson’s disease risks associated with dietary iron, manganese, and other nutrient intakes. Neurology. 2003; 60(11): 1761-1766. doi: 10.1212/01.wnl.0000068021.13945.7f
52. Pichler I, Del Greco MF, Gögele M, Lill CM, Bertram L, Do CB, et al. Serum iron levels and the risk of Parkinson disease: A Mendelian randomization study. PLoS Med. 2013; 10(6): e1001462. doi: 10.1371/journal.pmed.1001462
53. Cheng P, Yu J, Huang W, Bai S, Zhu X, Qi Z, et al. Dietary intake of iron, zinc, copper, and risk of Parkinson’s disease: A metaanalysis. Neurol Sci. 2015; 36(12): 2269-2275. doi: 10.1007/s10072-015-2349-0
54. Muñoz Y, Carrasco CM, Campos JD, Aguirre P, Núñez MT. Parkinson’s disease: The mitochondria-iron link. Parkinsons Dis. 2016; 2016: 7049108. doi: 10.1155/2016/7049108 55. Ramalingam M, Kim SJ. Reactive oxygen/nitrogen species and their functional correlations in neurodegenerative diseases. J Neural Transm (Vienna). 2012; 119(8): 891-910. doi: 10.1007/s00702-011-0758-7
55. Mezentsev YuA, Osipova OA. Review of current information impact of oxidative stress on premature aging. Current Problems of Health Care and Medical Statistics. 2022; 5: 249-269. (In Russ.). doi: 10.24412/2312-2935-2022-5-249-269
56. Bir A, Sen O, Anand S, Khemka VK, Banerjee P, Cappai R, et al. α-synuclein-induced mitochondrial dysfunction in isolated preparation and intact cells: Implications in the pathogenesis of Parkinson’s disease. J Neurochem. 2014; 131(6): 868-877. doi: 10.1111/jnc.12966
Review
For citations:
Salkov V.N. Causes of accumulation of excess iron in the structures of the substantia nigra of the brain in Parkinson’s disease. Acta Biomedica Scientifica. 2025;10(1):161-168. (In Russ.) https://doi.org/10.29413/ABS.2025-10.1.17
Views:
235
.png)
Email this article 
