Mechanism of cuproptosis in pathogenesis of Parkinson’s disease

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Parkinson’s disease is a high prevalent neurodegenerative disease. The exact pathogenesis of this disease remains to be fully elucidated; however, regardless of the underlying mechanisms, the ultimate outcome is the progressive loss of dopaminergic neurons. Cuproptosis is a recently discovered form of copper-induced regulated cell death. Its morphology, biochemical properties, and mechanism of action differ from known forms of cell death such as apoptosis, autophagy, necrosis, and pyroptosis. Copper binds to the lipoylated components of the tricarboxylic acid cycle, causing proteotoxic stress, which eventually results in cell cuproptosis. The pathological biochemical hallmarks of Parkinson’s disease include mitochondrial dysfunction and lower brain levels of copper and glutathione. These processes are intricately associated with the underlying mechanism of cuproptosis. However, the specific aspects of the interplay between the pathogenesis of Parkinson’s disease and cuproptosis have yet to be fully explored. The article summarizes the available evidence on cuproptosis as the cause of neuronal death in Parkinson’s disease, and its role in the pathogenesis of Parkinson’s disease. Cuproptosis offers a novel and promising approach to understanding the role of copper dysregulation in the pathogenesis of neurodegenerative diseases. A comprehensive understanding of the mechanisms underlying copper-induced cell death will facilitate the development of novel therapeutic strategies, particularly to address medical conditions associated with copper imbalance, including Wilson’s disease and Parkinson’s disease. The therapeutic potential of targeting cuproptosis using copper chelation strategies has already been confirmed in various experimental models that demonstrate significant improvement in cognitive functions and symptoms of the disease. The incorporation of the concept of cuproptosis into clinical practice promises to enhance diagnostic accuracy and treatment efficacy by personalizing medical approaches, facilitating early intervention, and enabling precise regulation of copper levels. The further investigation of the complex molecular mechanisms of cuproptosis, the development of specific biomarkers for the early detection of neurodegenerative diseases, and the optimization of therapeutic protocols to ensure the safety and efficacy of treatment are all essential. Addressing these challenges will play a pivotal role in the successful integration of novel scientific advances into clinical practice, thereby enhancing patient care and overall quality of life.

Full Text

Restricted Access

About the authors

Vladimir I. Vashchenko

Kirov Military Medical Academy

Email: vladimir-vaschenko@yandex.ru
ORCID iD: 0000-0002-3908-143X

Dr. Sci. (Biology)

Russian Federation, 6Zh, Akademika Lebedeva st., Saint Petersburg, 194044

Alexey B. Chukhlovin

Kirov Military Medical Academy

Email: alexei.chukh@mail.ru
ORCID iD: 0000-0001-9703-4378
SPIN-code: 3050-7030

MD, Dr. Sci. (Medicine), Professor

Russian Federation, 6Zh, Akademika Lebedeva st., Saint Petersburg, 194044

Petr D. Shabanov

Kirov Military Medical Academy

Author for correspondence.
Email: pdshabanov@mail.ru
ORCID iD: 0000-0003-1464-1127
SPIN-code: 8974-7477

MD, Dr. Sci. (Medicine), Professor

Russian Federation, 6Zh, Akademika Lebedeva st., Saint Petersburg, 194044

References

  1. Novikov NI, Brazhnik ES, Kichigina VF. Pathological correlates of cognitive decline in Parkinson’s disease: from molecules to neural networks. Biokhimiya. 2023;88(11):2289–2307. doi: 10.31857/S0320972523110180 EDN: MMXSXC
  2. Chen S, Fu J, Lai X, et al. Analyses of hospitalization in Alzheimer’s disease and Parkinson’s disease in a tertiary hospital. Front Public Health. 2023;11:1159110. doi: 10.3389/fpubh.2023.1159110 EDN: CJZXBU
  3. Cattaneo C, Jost WH. Pain in Parkinson’s disease: pathophysiology, classification and treatment. J Integr Neurosci. 2023;22(5):132. doi: 10.31083/j.jin2205132 EDN: QBAIMZ
  4. J Fu, X Lai, Y Huang, T Bao, J Yang, S Chen, X Chen, H Shang Meta-analysis and systematic review of peripheral platelet-associated biomarkers to explore the pathophysiology of Alzheimer’s disease. BMC Neurol. 2023;23:66. Published online 2023 Feb 11. doi: 10.1186/s12883-023-03099-5
  5. Pilkevich NB, Markovskaya VA, Yavorskaya OV, et al. Pathophysiological relationship of copper with neurodegenerative disorders (Review). Trace Elements in Medicine. 2023;24(3):22–30. doi: 10.19112/2413-6174-2023-24-3-22-30
  6. Popescu BO, Batzu L, Ruiz PJG, et al. Neuroplasticity in Parkinson’s disease. J Neural Transm (Vienna). 2024;131(11):1329–1339. doi: 10.1007/s00702-024-02813-y
  7. Patel R, Kompoliti K. Sex and Gender Differences in Parkinson’s Disease. Neurol Clin. 2023;41(2):371–379. doi: 10.1016/j.ncl.2022.12.001 EDN: XNYVSE
  8. Shabanov PD, Vashchenko VI. Biological role of microRNA-146a in viral infections. Modern strategy for the search of new safe pharmacological treatments. Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):145–174. doi: 10.17816/RCF192145-174 EDN: UQXNUP
  9. Levin OS, Fedorova NV. Parkinson’s Disease. 7th ed. Moscow: MEDpress-inform; 2017. 384 p. (In Russ.) ISBN: 978-5-00030-498-3
  10. Frost ED, Shi SX, Byroju VV, et al. Galantamine-memantine combination in the treatment of Parkinson’s disease dementia. Brain Sci. 2024;14(12):1163. doi: 10.3390/brainsci14121163 EDN: QTUQHU
  11. Domínguez-Fernández C, et al. Review of technological challenges in personalised medicine and early diagnosis of neurodegenerative disorders. Int J Mol Sci. 2023;24(4):3321. doi: 10.3390/ijms24043321
  12. Sul JH, Shin S, Kim HK, et al. Dopamine-conjugated extracellular vesicles induce autophagy in Parkinson disease. J Extracell Vesicles. 2024;13(12):e70018. doi: 10.1002/jev2.70018 EDN: GRMOAR
  13. Jiang Z, et al. β-Hydroxybutyrate alleviates pyroptosis in MPP/MPTP-induced Parkinson’s disease models via inhibiting STAT3/NLRP3/GSDMD pathway. Int Immunopharmacol. 2022;113(Pt B): 109451. doi: 10.1016/j.intimp.2022.109451 EDN: VZLLEA
  14. Huang Y, Wei J, Cooper A, Morris MJ. Parkinson’s disease: From genetics to molecular dysfunction and targeted therapeutic approaches. Genes Dis. 2022;10(3):786–798. doi: 10.1016/j.gendis.2021.12.015 EDN: ZNSBOZ
  15. Ma C, Wei X, Wang F, et al. Tumor necrosis factor α-induced protein 3 mediates inflammation and neuronal autophagy in Parkinson’s disease via the NFκB and mTOR pathways. Neurosci Lett. 2023;805:137223. doi: 10.1016/j.neulet.2023.137223 EDN: NNFOLS
  16. Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375(6586):1254–1261. doi: 10.1126/science.abf0529 EDN: LRZPSA
  17. Maung MT, Carlson A, Olea-Flores M, et al. The molecular and cellular basis of copper dysregulation and its relationship with human pathologies. FASEB J. 2021;35(9):e21810. doi: 10.1096/fj.202100273RR EDN: WPXIGD
  18. Lutsenko S, Roy S, Tsvetkov P. Mammalian copper homeostasis: physiological roles and molecular mechanisms. Physiol Rev. 2025;105(1):441–491. doi: 10.1152/physrev.00011.2024 EDN: UUJTRZ
  19. An Y, Li S, Huang X, et al. The role of copper homeostasis in brain disease. Int J Mol Sci. 2022;23(22):13850. doi: 10.3390/ijms232213850 EDN: WLRSSJ
  20. Ameh T, Gibb M, Stivens D, et al. Silver and copper nanoparticles induce oxidative stress in bacteria and mammalian cells. Nanomaterials. 2022;12(14):2402. doi: 10.3390/nano12142402 EDN: MOCVNB
  21. Gromadzka G, Tarnacka B, Flaga A, et al. Copper Dyshomeostasis in Neurodegenerative Diseases-Therapeutic Implications. Int J Mol Sci. 2020;21(23):9259. doi: 10.3390/ijms21239259 EDN: DJDZWL
  22. Shen C, Zheng ZG, Shao J, et al. Mechanistic investigation of the differential synergistic neurotoxicity between pesticide metam sodium and copper or zinc. Chemosphere. 2023;328:138430. doi: 10.1016/j.chemosphere.2023.138430 EDN: IYNXWG
  23. Cruces-Sande A, Rodriguez-Perez AI, Herbello-Hermelo P, et al. Copper increases brain oxidative stress and enhances the ability of 6-hydroxydopamine to cause dopaminergic degeneration in a rat model of Parkinson’s disease. Mol Neurobiol. 2019;56(4):2845–2854. doi: 10.1007/s12035-018-1274-7 EDN: ZRJHCJ
  24. Zhang M, Meng W, Liu C, et al. Identification of cuproptosis clusters and integrative analyses in Parkinson disease. Brain Sci. 2023;13(7):1015. doi: 10.3390/brainsci13071015 EDN: BOXOQD
  25. Guo H, Wang Y, Cui H, et al. Copper induces spleen damage through modulation of oxidative stress, apoptosis, DNA damage, and inflammation. Biol Trace Elem Res. 2024;203(8):4428-4428; doi: 10.1007/s12011-024-04500-1 EDN: QDGYDN
  26. He Q, Yang J, Pan X, et al. Biochanin A protects against iron overload associated knee osteoarthritis via regulating iron levels and NRF2/System xc-/GPX4 axis. Biomed Pharm. 2023;157:113915. doi: 10.1016/j.biopha.2022.113915 EDN: AWVSND
  27. Wan XX, Wan X, Wan XX, et al. Copper metabolism and cuproptosis: molecular mechanisms and therapeutic perspectives in neurodegenerative diseases. Curr Med Sci. 2024;44(1):28–50. doi: 10.1007/s11596-024-2832-z EDN: JPCUJM
  28. Pyatha S, Kim H, Lee D, Kim K. Association between heavy metal exposure and Parkinson’s disease: a review of the mechanisms related to oxidative stress. Antioxidants (Basel). 2022;11(12):2467. doi: 10.3390/antiox11122467 EDN: IVWJHJ
  29. Wang Y, Li D, Xu K, et al. Copper homeostasis and neurodegenerative diseases. Neural Regen Res. 2025;20(11):3124–3143. doi: 10.4103/NRR.NRR-D-24-00642 EDN: DIUBJB
  30. Cole-Hunter T, Zhang J, So R, et al. Long-term air pollution exposure and Parkinson’s disease mortality in a large pooled European cohort: An ELAPSE study. Environ Int. 2023;171:107667. doi: 10.1016/j.envint.2022.107667 EDN: LTLVBM
  31. Li S, Ritz B, Gun J, et al. Proximity to residential and workplace pesticides application and the risk of progression of Parkinson’s diseases in Central California. Sci Total Environ. 2023;864:160851. doi: 10.1016/j.scitotenv.2022.160851 EDN: BJKFYW
  32. Pitton Rissardo J, Caprara ALF. Neuroimaging techniques in differentiating Parkinson’s disease from drug-induced parkinsonism: A Comprehensive Review. Clin Pract. 2023;13(6):1427–1448. doi: 10.3390/clinpract13060128 EDN: HCLNJJ
  33. Ilyechova EY, Miliukhina IV, Orlov IA, et al. A low blood copper concentration is a co-morbidity burden factor in Parkinson’s disease development. Neurosci Res. 2018;135:54–62. doi: 10.1016/j.neures.2017.11.011 EDN: KIAZDY
  34. Kim MJ, Oh SB, Kim J. Association of metals with the risk and clinical characteristics of Parkinson’s disease. Parkinsonism Relat Disord. 2018;55:117–121. doi: 10.1016/j.parkreldis.2018.05.022 EDN: ANGVPN
  35. 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. doi: 10.1111/j.1471-4159.1989.tb07264.x
  36. Uitti RJ, Rajput AH, Rozdilsky B, et al. Regional metal concentrations in Parkinson’s disease, other chronic neurological diseases, and control brains. Can J Neurol Sci. 1989;16(3):310–314. doi: 10.1017/S0317167100029140
  37. Loeffler DA, LeWitt PA, Juneau PL, et al. Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders. Brain Res. 1996;738(2):265–274. doi: 10.1016/S0006-8993(96)00782-2 EDN: VJSHFB
  38. Ayton S, Lei P, Duce JA, et al. Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann Neurol. 2013;73(4): 554–559. doi: 10.1002/ana.23817
  39. Davies KM, Mercer JF, Chen N, Double KL. Copper dyshomoeostasis in Parkinson’s disease: Implications for pathogenesis and indications for novel therapeutics. Clin Sci (Lond). 2016;130(8):565–574. doi: 10.1042/CS20150153 EDN: WUHTCJ
  40. Harris ZL, Klomp LW, Gitlin JD. Aceruloplasminemia: An inherited neurodegenerative disease with impairment of iron homeostasis. Am J Clin Nutr. 1998;67(5):972S–977S. doi: 10.1093/ajcn/67.5.972S EDN: LMXCJR
  41. Patel BN, Dunn RJ, Jeong SY, et al. Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J Neurosci. 2002;22(15):6578–6586. doi: 10.1523/JNEUROSCI.22-15-06578.2002
  42. Xu X, Pin S, Gathinji M, et al. Aceruloplasminemia: An inherited neurodegenerative disease with impairment of iron homeostasis. Ann NY Acad Sci. 2004;1012(1):299–305. doi: 10.1196/annals.1306.024
  43. Collins JF, Prohaska JR, Knutson MD. Metabolic crossroads of iron and copper. Nutr Rev. 2010;68(3):133–147. doi: 10.1111/j.1753-4887.2010.00271.x
  44. Szerdahelyi P, Kasa P. Histochemical demonstration of copper in normal rat brain and spinal cord. Evidence of localization in glial cells. Histochemistry. 1986;85(4):341–347. doi: 10.1007/BF00493487 EDN: OEUYSZ
  45. Lewinska-Preis L, Jablonska M, Fabianska MJ, Kita A. Bioelements and mineral matter in human livers from the highly industrialized region of the upper Silesia coal basin (Poland). Environ Geochem Health. 2011;33(6):595–611. doi: 10.1007/s10653-011-9373-7 EDN: UVXWWA
  46. Bulcke F, Dringen R, Scheiber IF. Neurotoxicity of copper. Adv Neurobiol. 2017;18:313–343. doi: 10.1007/978-3-319-60189-2_16 EDN: YGXFNM
  47. Navarro JA, Schneuwly S. Copper and zinc homeostasis: Lessons from Drosophila melanogaster. Front Genet. 2017;8:223. doi: 10.3389/fgene.2017.00223 EDN: YESEHZ
  48. Pohanka M. Copper and copper nanoparticles toxicity and their impact on basic functions in the body. Bratisl Lek Listy. 2019;120(6):397–409. doi: 10.4149/BLL_2019_065 EDN: CAMAQS
  49. Roeser HP, Lee GR, Nacht S, Cartwright GE. The role of ceruloplasmin in iron metabolism. J Clin Invest. 1970;49(12):2408–2417. doi: 10.1172/JCI106460
  50. D’Ambrosi N, Rossi L. Copper at synapse: Release, binding and modulation of neurotransmission. Neurochem Int. 2015;90:36–45. doi: 10.1016/j.neuint.2015.07.006 EDN: VGSYAF
  51. Scheiber IF, Mercer JF, Dringen R. Metabolism and functions of copper in brain. Prog Neurobiol. 2014;116:33–57. doi: 10.1016/j.pneurobio.2014.01.002 EDN: SPLBGN
  52. De Lazzari F, Bubacco L, Whitworth AJ, Bisaglia M. Superoxide radical dismutation as new therapeutic strategy in Parkinson’s disease. Aging Dis. 2018;9(4):716–728. doi: 10.14336/AD.2017.1018 EDN: VIDMEQ
  53. Ackerman CM, Chang CJ. Copper signaling in the brain and beyond. J Biol Chem. 2018;293(13):4628–4635. doi: 10.1074/jbc.R117.000176 EDN: YFKWPR
  54. Rae TD, Schmidt PJ, Pufahl RA, et al. Undetectable intracellular free copper: The requirement of a copper chaperone for superoxide dismutase. Science. 1999;284(5415):805–808. doi: 10.1126/science.284.5415.805 EDN: DAPQYB
  55. Scheuhammer AM, Cherian MG. Effects of heavy metal cations, sulfhydryl reagents and other chemical agents on striatal d2 dopamine receptors. Biochem Pharmacol. 1985;34(19):3405–3413. doi: 10.1016/0006-2952(85)90710-5
  56. Kehrer JP. The Haber-Weiss reaction and mechanisms of toxicity. Toxicology. 2000;149(1):43–50. doi: 10.1016/s0300-483x(00)00231-6
  57. Bisaglia M, Filograna R, Beltramini M, Bubacco L. Are dopamine derivatives implicated in the pathogenesis of Parkinson’s disease? Ageing Res Rev. 2014;13:107–114. doi: 10.1016/j.arr.2013.12.009 EDN: DIUODV
  58. Mosharov EV, Borgkvist A, Sulzer D. Presynaptic effects of levodopa and their possible role in dyskinesia. Mov Disord. 2015;30(1):45–53. doi: 10.1002/mds.26103 EDN: VGXOVT
  59. Monzani E, Nicolis S, Dell’Acqua S, et al. Dopamine, oxidative stress and protein-quinone modifications in Parkinson’s and other neurodegenerative diseases. Angew Chem Int Ed Engl. 2019;58(20):6512–6527. doi: 10.1002/anie.201811122 EDN: GEHFRP
  60. Palumbo A, d’Ischia M, Misuraca G, Prota G. Effect of metal ions on the rearrangement of dopachrome. Biochim Biophys Acta. 1987;925(2):203–209. doi: 10.1016/0304-4165(87)90110-3
  61. Warren PJ, Earl CJ, Thompson RH. The distribution of copper in human brain. Brain. 1960;83(4):709–717. doi: 10.1093/brain/83.4.709 EDN: ILWWSX
  62. Davies KM, Hare DJ, Cottam V, et al. Localization of copper and copper transporters in the human brain. Metallomics. 2013;5(1):43–51. doi: 10.1039/c2mt20151h
  63. Krebs N, Langkammer C, Goessler W, et al. Assessment of trace elements in human brain using inductively coupled plasma mass spectrometry. J Trace Elem Med Biol. 2014;28(1):1–7. doi: 10.1016/j.jtemb.2013.09.006 EDN: SOUAVB
  64. Pham AN, Waite TD. Cu(II)-catalyzed oxidation of dopamine in aqueous solutions: Mechanism and kinetics. J Inorg Biochem. 2014;137:74–84. doi: 10.1016/j.jinorgbio.2014.03.018 EDN: SQAPYL
  65. Dodani SC, Domaille DW, Nam CI, et al. Calcium-dependent copper redistributions in neuronal cells revealed by a fluorescent copper sensor and x-ray fluorescence microscopy. Proc Natl Acad Sci USA. 2011;108(15):5980–5985. doi: 10.1073/pnas.1009932108
  66. Deas E, Cremades N, Angelova PR, et al. Alpha-synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson’s disease. Antioxid Redox Signal. 2016;24(7):376–391. doi: 10.1089/ars.2015.6343 EDN: WVBERJ
  67. Karimi-Moghadam A, Charsouei S, Bell B, Jabalameli MR. Parkinson disease from mendelian forms to genetic susceptibility: New molecular insights into the neurodegeneration process. Cell Mol Neurobiol. 2018;38(6):1153–1178. doi: 10.1007/s10571-018-0587-4 EDN: YIRMYP
  68. Bisaglia M, Bubacco L. Copper ions and Parkinson’s Disease: Why is homeostasis so relevant? Biomolecules. 2020;10(2):195. doi: 10.3390/biom10020195
  69. Wu KM, Xu QH, Liu YQ, et al. Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease. Science. 2025;387(6736):892–900. doi: 10.1126/science.adp3645
  70. Uversky VN, Li J, Fink AL. Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular link between Parkinson’s disease and heavy metal exposure. J Biol Chem. 2001;276(47):44284–44296. doi: 10.1074/jbc.M105343200 EDN: LGYPRV
  71. 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 EDN: MIFZYP
  72. Kawahara M, Kato-Negishi M, Tanaka K. Cross talk between neurometals and amyloidogenic proteins at the synapse and the pathogenesis of neurodegenerative diseases. Metallomics. 2017;9(6):619–633. doi: 10.1039/c7mt00046d EDN: YFSYCF
  73. Sung YH, Rospigliosi C, Eliezer D. NMR mapping of copper binding sites in alpha-synuclein. Biochim Biophys Acta. 2006;1764(1): 5–12. doi: 10.1016/j.bbapap.2005.11.003 EDN: MCNQMT
  74. McDowall JS, Brown DR. Alpha-synuclein: Relating metals to structure, function and inhibition. Metallomics. 2016;8(4):385–397. doi: 10.1039/c6mt00026f EDN: WUURUP
  75. Rasia RM, Bertoncini CW, Marsh D, et al. Structural characterization of copper (II) binding to alpha-synuclein: Insights into the bioinorganic chemistry of Parkinson’s disease. Proc Natl Acad Sci USA. 2005;102(12):4294–4299. doi: 10.1073/pnas.0407881102 EDN: MIFZTZ
  76. Camponeschi F, Valensin D, Tessari I, et al. Copper(I)-alpha-synuclein interaction: Structural description of two independent and competing metal binding sites. Inorg Chem. 2013;52(3):1358–1367. doi: 10.1021/ic302050m EDN: RKTGHZ
  77. Binolfi A, Valiente-Gabioud AA, Duran R, et al. Exploring the structural details of Cu(I) binding to alpha-synuclein by NMR spectroscopy. J Am Chem Soc. 2011;133(2):194–196. doi: 10.1021/ja107842f EDN: OAFOAB
  78. Bortolus M, Bisaglia M, Zoleo A, et al. Structural characterization of a high affinity mononuclear site in the copper (II)-alpha-synuclein complex. J Am Chem Soc. 2010;132(51):18057–18066. doi: 10.1021/ja103338n EDN: MPLALA
  79. Anderson JP, Walker DE, Goldstein JM, et al. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem. 2006;281(40):29739–29752. doi: 10.1074/jbc.M600933200
  80. Bartels T, Choi JG, Selkoe DJ. Alpha-synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature. 2011;477(7362):107–110. doi: 10.1038/nature10324
  81. Kang L, Moriarty GM, Woods LA, et al. N-terminal acetylation of alpha-synuclein induces increased transient helical propensity and decreased aggregation rates in the intrinsically disordered monomer. Protein Sci. 2012;21(7):911–917. doi: 10.1002/pro.2088 EDN: PGWCKT
  82. Maltsev AS, Ying J, Bax A. Impact of N-terminal acetylation of alpha-synuclein on its random coil and lipid binding properties. Biochemistry. 2012;51(25):5004–5013. doi: 10.1021/bi300642h EDN: NSPELH
  83. Dikiy I, Eliezer D. N-terminal acetylation stabilizes N-terminal helicity in lipid- and micelle-bound alpha-synuclein and increases its affinity for physiological membranes. J Biol Chem. 2014;289(6):3652–3665. doi: 10.1074/jbc.M113.512459
  84. Miotto MC, Valiente-Gabioud AA, Rossetti G, et al. Copper binding to the N-terminally acetylated, naturally occurring form of alpha-synuclein induces local helical folding. J Am Chem Soc. 2015;137(20):6444–6447. doi: 10.1021/jacs.5b01911
  85. Valensin D, Dell’Acqua S, Kozlowski H, Casella L. Coordination and redox properties of copper interaction with alpha-synuclein. J Inorg Biochem. 2016;163:292–300. doi: 10.1016/j.jinorgbio.2016.04.012 EDN: XUKSCL
  86. Mason RJ, Paskins AR, Dalton CF, Smith DP. Copper binding and subsequent aggregation of alpha-synuclein are modulated by N-terminal acetylation and ablated by the H50Q missense mutation. Biochemistry. 2016;55(34):4737–4741. doi: 10.1021/acs.biochem.6b00708 EDN: XTJCSX
  87. Santner A, Uversky VN. Metalloproteomics and metal toxicology of alpha-synuclein. Metallomics. 2010;2(6):378–392. doi: 10.1039/b926659c EDN: PFXBVT
  88. Breydo L, Uversky VN. Role of metal ions in aggregation of intrinsically disordered proteins in neurodegenerative diseases. Metallomics. 2011;3(11):1163–1180. doi: 10.1039/c1mt00106j EDN: PEEFDX
  89. Vashchenko VI, Chukhlovin AB, Shabanov PD. Cuproptosis – a special form of regulated copper-dependent cell death. Prospects for pharmacological correction in human diseases. Psychopharmacology and Biological Narcology. 2024;15(4):287–324. doi: 10.17816/phbn6418542024 EDN: XVNWIQ
  90. Shen Y, Lv QK, Xie WY. Circadian disruption and sleep disorders in neurodegeneration. Transl Neurodegener. 2023;12(1):8. doi: 10.1186/s40035-023-00340-6 EDN: WUYUGP
  91. Speksnijder EM, Bisschop PH, Siegelaar SE, et al. Circadian desynchrony and glucose metabolism. J Pineal Res. 2024;76(4):e12956. doi: 10.1111/jpi.12956 EDN: UIWNXI
  92. Nassan M, Videnovic A. Circadian rhythms in neurodegenerative disorders. Nat Rev Neurol. 2022;18(1):7–24. doi: 10.1038/s41582-021-00577-7 EDN: OTTETA
  93. Bass J. Interorgan rhythmicity as a feature of healthful metabolism. Cell Metab. 2024;36(4):655–669. doi: 10.1016/j.cmet.2024.01.009 EDN: GESKXO
  94. Rathor P, Ratnasekhar Ch. Metabolic basis of circadian dysfunction in Parkinson’s disease. Biology. 2023;12(10):1294. doi: 10.3390/biology12101294 EDN: IPDFOY
  95. Gromadzka G, Wilkaniec A, Tarnacka B, et al. The role of glia in Wilson’s disease: clinical, neuroimaging, neuropathological and molecular perspectives. Int J Mol Sci. 2024;25(14):7545. doi: 10.3390/ijms25147545 EDN: HFIZEJ
  96. Wang T, Sun Y, Dettmer U. Astrocytes in Parkinson’s disease: from role to possible intervention. Cells. 2023;12(19):2336. doi: 10.3390/cells12192336 EDN: GIMYHW
  97. Chen Z, Liu J, Zheng M, et al. TRIM24-DTNBP1-ATP7A mediated astrocyte cuproptosis in cognition and memory dysfunction caused by Y2O3. Sci Total Environ. 2024;954:176353. doi: 10.1016/j.scitotenv.2024.176353 EDN: RXNTJA
  98. Trist BG, Davies KM, Cottam V, et al. Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson’s disease brain. Acta Neuropathol. 2017;134(1):113–127. doi: 10.1007/s00401-017-1726-6 EDN: YFOCFI
  99. Nishiyama K, Murayama S, Shimizu J, et al. Cu/Zn superoxide dismutase-like immunoreactivity is present in Lewy bodies from Parkinson disease: A light and electron microscopic immunocytochemical study. Acta Neuropathol. 1995;89(6):471–474. doi: 10.1007/BF00571500
  100. Roudeau S, Chevreux S, Carmona A, Ortega R. Reduced net charge and heterogeneity of pi isoforms in familial amyotrophic lateral sclerosis mutants of copper/zinc superoxide dismutase. Electrophoresis. 2015;36(19):2482–2488. doi: 10.1002/elps.201500187
  101. National Research Council. Copper in Drinking Water. Washington, DC: National Academy Press; 2000. 162 p. doi: 10.17226/9782
  102. Tümer Z, Moller LB. Menkes disease. Eur J Hum Genet. 2010;18(5):511–518. doi: 10.1038/ejhg.2009.187
  103. Kaler SG. ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol. 2011;7(1):15–29. doi: 10.1038/nrneurol.2010.180 EDN: PMAINB
  104. Litwin T, Gromadzka G, Szpak GM, et al. Brain metal accumulation in Wilson’s disease. J Neurol Sci. 2013;329(1-2):55–58. doi: 10.1016/j.jns.2013.03.021
  105. Bandmann O, Weiss KH, Kaler SG. Wilson’s disease and other neurological copper disorders. Lancet Neurol. 2015;14(1):103–113. doi: 10.1016/S1474-4422(14)70190-5 EDN: UVTOVT
  106. Beauchamp LC, Liu XM, Vella LJ, et al. ATH434 Rescues Pre-motor Hyposmia in a Mouse Model of Parkinsonism. Neurotherapeutics. 2022;19(6):1966–1975. doi: 10.1007/s13311-022-01300-0 EDN: QUZIMK
  107. Huang M, Zhang Y, Liu X. The mechanism of cuproptosis in Parkinson’s disease. Ageing Res Rev. 2024;95:102214. doi: 10.1016/j.arr.2024.102214 EDN: FQFTZQ
  108. Jomova K, Alomar SY, Nepovimova E, et al. Heavy metals: toxicity and human health effects. Arch Toxicol. 2025;99(1):153–209. doi: 10.1007/s00204-024-03903-2 EDN: ADNFYZ
  109. Li SR, Tao SY, Li Q, et al. Harnessing nanomaterials for copper-induced cell death. Biomaterials. 2025;313:122805. doi: 10.1016/j.biomaterials.2024.122805 EDN: JJBIXV
  110. Espay AJ, Morgante F, Merola A, et al. Levodopa-induced dyskinesia in Parkinson disease: current and evolving concepts. Ann Neurol. 2018;84(6):797–811. doi: 10.1002/ana.25364
  111. Wang C, Zhang K, Cai B, et al. VAMP2 chaperones alpha-synuclein in synaptic vesicle co-condensates. Nat Cell Biol. 2024;26(8):1287–1295. doi: 10.1038/s41556-024-01456-1 EDN: HYFLPM
  112. Wang X, Yang G, Lai Y, et al. Exploring the hub genes and potential mechanisms of complement system-related genes in Parkinson disease: based on transcriptome sequencing and mendelian randomization. J Mol Neurosci. 2024;74(4):95. doi: 10.1007/s12031-024-02272-w EDN: NOTOJR
  113. Zhang H, Nagai J, Hao L, Jiang X. Identification of key genes and immunological features associated with copper metabolism in Parkinson’s disease by bioinformatics analysis. Mol Neurobiol. 2024;61(2):799–811. doi: 10.1007/s12035-023-03565-8 EDN: JYCKCH

Supplementary files

Supplementary Files
Action
1. JATS XML
2. Fig. 1. Physiological processes involving the redox activity of copper. AO, aminoxidase; COX, cytochrome c oxidase; ЦП, ceruloplasmin; СОД, superoxide dismutase (adapted from М. Bisaglia et al. [68]).

Download (111KB)
3. Fig. 2. Сopper metabolism in human body. ГЭБ, blood-brain barrier; КЛБ, blood-cerebrospinal fluid barrier; CTR1, copper transporter in hepatic vascular cells; ЦП, ceruloplasmin; hCTR1, copper ion transporter in the gastrointestinal tract (adapted from М. Bisaglia et al. [68]).

Download (268KB)
4. Fig. 3. Intracellular processes associated with the redox activity of copper. ЭПР, endoplasmic reticulum; GSH, glutathione; CTR1, copper transporter; ATP7A, ATP7B, adenosine triphosphatases 7A and 7B; Atox1, transporter; CCS, copper chaperone; COX, cytochrome c oxidase; МВ, microvesicle; MT, metallothionein; СОД, superoxide dismutase (adapted from М. Bisaglia et al. [68]).

Download (220KB)
5. Fig. 4. Interaction with copper ions triggered by cuproptosis in pathogenesis of Parkinson’s disease. Alpha-synuclein (α-syn); Parkinson’s disease (БП); active oxygen form (АФК); dopamine (ДА). © 2025 Neural Regeneration Research. Adapted from [doi: 10.4103/NRR.NRR-D-24-00642]. Distributed under CC BY-ND 4.0 license.

Download (208KB)
6. Fig. 5. Effect of circadian rhythms on non-motor symptoms of Parkison’s disease.

Download (234KB)
7. Fig. 6. Hypothesized pattern of yttrium oxide-induced astrocyte cuproptosis. Y2O3 NPs, yttrium oxide nanoparticles; TRIM24, DTNBP1, copper transfer inhibitors (adapted from Z. Chen et al. [97]).

Download (183KB)
8. Fig. 7. Dysregulation of copper homeostasis in pathogenesis of Parkinson’s disease. α-syn, alpha-synuclein.

Download (111KB)
9. Fig. 8. General mechanism of copper regulation and cuproptosis in pathogenesis of Parkinson’s disease. TNF-α, tumor necrosis factor α; ЭТЦ, mitochondrial electron transport chain; NO, nitrous oxide; IL-6, IL-1β, interleukins.

Download (291KB)

Copyright (c) 2025 Eco-Vector

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 84654 от 01.02.2023 г