Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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ATF4-activated parkin induction contributes to deferasirox-mediated cytoprotection in Parkinson's disease

  • Sangwoo Ham (Department of Pharmacology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine) ;
  • Ji Hun Kim (Department of Pharmacology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine) ;
  • Heejeong Kim (Department of Pharmacology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine) ;
  • Jeong-Yong Shin (Department of Pharmacology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine) ;
  • Yunjong Lee (Department of Pharmacology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine)
  • Received : 2022.08.29
  • Accepted : 2022.11.15
  • Published : 2023.04.15
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Abstract

The E3 ubiquitin ligase parkin plays neuroprotective functions in the brain and the deficits of parkin's ligase function in Parkinson's disease (PD) is associated with reduced survival of dopaminergic neurons. Thus, compounds enhancing parkin expression have been developed as potential neuroprotective agents that prevent ongoing neurodegeneration in PD environments. Besides, iron chelators have been shown to have neuroprotective effects in diverse neurological disorders including PD. Although repression of iron accumulation and oxidative stress in brains has been implicated in their marked neuroprotective potential, molecular mechanisms of iron chelator's neuroprotective function are largely unexplored. Here, we show that the iron chelator deferasirox provides cytoprotection against oxidative stress through enhancing parkin expression under basal conditions. Parkin expression is required for cytoprotection against oxidative stress in SH-SY5Y cells with deferasirox treatment as confirmed by abolished deferasirox's cytoprotective effect after parkin knockdown by shRNA. Similar to the previously reported parkin inducing compound diaminodiphenyl sulfone, deferasirox-mediated parkin expression was induced by activation of the PERK-ATF4 pathway, which is associated with and stimulated by mild endoplasmic reticulum stress. The translational potential of deferasirox for PD treatment was further evaluated in cultured mouse dopaminergic neurons. There was a robust ATF4 activation and parkin expression in response to deferasirox treatment in dopaminergic neurons under basal conditions. Consequently, the enhanced parkin expression by deferasirox provided substantial neuroprotection against 6-hydroxydopamine-induced oxidative stress. Taken together, our study results revealed a novel mechanism through which an iron chelator, deferasirox induces neuroprotection. Since parkin function in the brain is compromised in PD and during aging, maintenance of parkin expression through the iron chelator treatment could be beneficial by increasing dopaminergic neuronal survival.

Keywords

Acknowledgement

This research was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP) (2018R1D1A1B07046762), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) and Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (HU22C0143000022).

References

  1. Grayson M (2016) Parkinson's disease. Nature 538:S1. https://doi.org/10.1038/538S1a 
  2. Lang AE, Lozano AM (1998) Parkinson's disease. First of two parts. N Engl J Med 339:1044-1053. https://doi.org/10.1056/nejm199810083391506 
  3. Lang AE, Lozano AM (1998) Parkinson's disease. Second of two parts. N Engl J Med 339:1130-1143. https://doi.org/10.1056/nejm199810153391607 
  4. Dawson TM (2006) Parkin and defective ubiquitination in Parkinson's disease. J Neural Transm Suppl 209-213. https://doi.org/10.1007/978-3-211-45295-0_32 
  5. Moore DJ (2006) Parkin: a multifaceted ubiquitin ligase. Biochem Soc Trans 34:749-753. https://doi.org/10.1042/bst0340749 
  6. Chung KK, Thomas B, Li X, Pletnikova O, Troncoso JC, Marsh L, Dawson VL, Dawson TM (2004) S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science 304:1328-1331. https://doi.org/10.1126/science.1093891 
  7. Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM (2010) Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. Proc Natl Acad Sci U S A 107:16691-16696. https://doi.org/10.1073/pnas.1006083107 
  8. Imam SZ, Zhou Q, Yamamoto A, Valente AJ, Ali SF, Bains M, Roberts JL, Kahle PJ, Clark RA, Li S (2011) Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease. J Neurosci 31:157-163. https://doi.org/10.1523/jneurosci.1833-10.2011 
  9. Lee YI, Kang H, Ha YW, Chang KY, Cho SC, Song SO, Kim H, Jo A, Khang R, Choi JY, Lee Y, Park SC, Shin JH (2016) Diaminodiphenyl sulfone-induced parkin ameliorates age-dependent dopaminergic neuronal loss. Neurobiol Aging 41:1-10. https://doi.org/10.1016/j.neurobiolaging.2015.11.008 
  10. Golbe LI, Di Iorio G, Sanges G, Lazzarini AM, La Sala S, Bonavita V, Duvoisin RC (1996) Clinical genetic analysis of Parkinson's disease in the Contursi kindred. Ann Neurol 40:767-775. https://doi.org/10.1002/ana.410400513 
  11. Venderova K, Park DS (2012) Programmed cell death in Parkinson's disease. Cold Spring Harb Perspect Med 2. https://doi.org/10.1101/cshperspect.a009365 
  12. Lee Y, Karuppagounder SS, Shin JH, Lee YI, Ko HS, Swing D, Jiang H, Kang SU, Lee BD, Kang HC, Kim D, Tessarollo L, Dawson VL, Dawson TM (2013) Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat Neurosci 16:1392-1400. https://doi.org/10.1038/nn.3500 
  13. Stevens DA, Lee Y, Kang HC, Lee BD, Lee YI, Bower A, Jiang H, Kang SU, Andrabi SA, Dawson VL, Shin JH, Dawson TM (2015) Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration. Proc Natl Acad Sci U S A 112:11696-11701. https://doi.org/10.1073/pnas.1500624112 
  14. Pirooznia SK, Yuan C, Khan MR, Karuppagounder SS, Wang L, Xiong Y, Kang SU, Lee Y, Dawson VL, Dawson TM (2020) PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of parkin or PINK1 deficiency. Mol Neurodegener 15:17. https://doi.org/10.1186/s13024-020-00363-x 
  15. Narendra D, Walker JE, Youle R (2012) Mitochondrial quality control mediated by PINK1 and parkin: links to parkinsonism. Cold Spring Harb Perspect Biol 4. https://doi.org/10.1101/cshperspect.a011338 
  16. Winklhofer KF (2014) Parkin and mitochondrial quality control: toward assembling the puzzle. Trends Cell Biol 24:332-341. https://doi.org/10.1016/j.tcb.2014.01.001 
  17. Bouman L, Schlierf A, Lutz AK, Shan J, Deinlein A, Kast J, Galehdar Z, Palmisano V, Patenge N, Berg D, Gasser T, Augustin R, Trumbach D, Irrcher I, Park DS, Wurst W, Kilberg MS, Tatzelt J, Winklhofer KF (2011) Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ 18:769-782. https://doi.org/10.1038/cdd.2010.142 
  18. Ham S, Lee YI, Jo M, Kim H, Kang H, Jo A, Lee GH, Mo YJ, Park SC, Lee YS, Shin JH, Lee Y (2017) Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson's disease model. Sci Rep 7:525. https://doi.org/10.1038/s41598-017-00614-w 
  19. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L (2014) The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 13:1045-1060. https://doi.org/10.1016/s1474-4422(14)70117-6 
  20. Mezzaroba L, Alfieri DF, Colado Simao AN, Vissoci Reiche EM (2019) The role of zinc, copper, manganese and iron in neurodegenerative diseases. Neurotoxicology 74:230-241. https://doi.org/10.1016/j.neuro.2019.07.007 
  21. Smith MA, Harris PL, Sayre LM, Perry G (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A 94:9866-9868. https://doi.org/10.1073/pnas.94.18.9866 
  22. Deas E, Cremades N, Angelova PR, Ludtmann MH, Yao Z, Chen S, Horrocks MH, Banushi B, Little D, Devine MJ, Gissen P, Klenerman D, Dobson CM, Wood NW, Gandhi S, Abramov AY (2016) Alpha-synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson's Disease. Antioxid Redox Signal 24:376-391. https://doi.org/10.1089/ars.2015.6343 
  23. Yarjanli Z, Ghaedi K, Esmaeili A, Rahgozar S, Zarrabi A (2017) Iron oxide nanoparticles may damage to the neural tissue through iron accumulation, oxidative stress, and protein aggregation. BMC Neurosci 18:51. https://doi.org/10.1186/s12868-017-0369-9 
  24. Sakamoto K, Suzuki T, Takahashi K, Koguchi T, Hirayama T, Mori A, Nakahara T, Nagasawa H, Ishii K (2018) Iron-chelating agents attenuate NMDA-Induced neuronal injury via reduction of oxidative stress in the rat retina. Exp Eye Res 171:30-36. https://doi.org/10.1016/j.exer.2018.03.008 
  25. Jimenez-Solas T, Lopez-Cadenas F, Aires-Mejia I, Caballero-Berrocal JC, Ortega R, Redondo AM, Sanchez-Guijo F, Muntion S, Garcia-Martin L, Albarran B, Alonso JM, Del Canizo C, Hernandez-Hernandez A, Diez-Campelo M (2019) Deferasirox reduces oxidative DNA damage in bone marrow cells from myelodysplastic patients and improves their differentiation capacity. Br J Haematol 187:93-104. https://doi.org/10.1111/bjh.16013 
  26. Miao J, Xu M, Kuang Y, Pan S, Hou J, Cao P, Duan X, Chang Y, Hasem H, Zhou N, Tan K, Fan Y (2020) Deferasirox protects against hydrogen peroxide-induced cell apoptosis by inhibiting ubiquitination and degradation of p21(WAF1/CIP1). Biochem Biophys Res Commun 524:736-743. https://doi.org/10.1016/j.bbrc.2020.01.155 
  27. Dexter DT, Statton SA, Whitmore C, Freinbichler W, Weinberger P, Tipton KF, Della Corte L, Ward RJ, Crichton RR (2011) Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson's disease after peripheral administration. J Neural Transm (Vienna) 118:223-231. https://doi.org/10.1007/s00702-010-0531-3 
  28. Kim H, Shin JY, Jo A, Kim JH, Park S, Choi JY, Kang HC, Dawson VL, Dawson TM, Shin JH, Lee Y (2021) Parkin interacting substrate phosphorylation by c-Abl drives dopaminergic neurodegeneration. Brain 144:3674-3691. https://doi.org/10.1093/brain/awab356 
  29. Cappellini MD (2007) Exjade(R) (deferasirox, ICL670) in the treatment of chronic iron overload associated with blood transfusion. Ther Clin Risk Manag 3:291-299. https://doi.org/10.2147/tcrm.2007.3.2.291 
  30. Loreal O, Turlin B, Pigeon C, Moisan A, Ropert M, Morice P, Gandon Y, Jouanolle AM, Verin M, Hider RC, Yoshida K, Brissot P (2002) Aceruloplasminemia: new clinical, pathophysiological and therapeutic insights. J Hepatol 36:851-856. https://doi.org/10.1016/s0168-8278(02)00042-9 
  31. Mariani R, Arosio C, Pelucchi S, Grisoli M, Piga A, Trombini P, Piperno A (2004) Iron chelation therapy in aceruloplasminaemia: study of a patient with a novel missense mutation. Gut 53:756-758. https://doi.org/10.1136/gut.2003.030429 
  32. Ward RJ, Dexter D, Florence A, Aouad F, Hider R, Jenner P, Crichton RR (1995) Brain iron in the ferrocene-loaded rat: its chelation and influence on dopamine metabolism. Biochem Pharmacol 49:1821-1826. https://doi.org/10.1016/0006-2952(94)00521-m 
  33. Hua Y, Keep RF, Hoff JT, Xi G (2008) Deferoxamine therapy for intracerebral hemorrhage. Acta Neurochir Suppl 105:3-6. https://doi.org/10.1007/978-3-211-09469-3_1 
  34. Selim M (2009) Deferoxamine mesylate: a new hope for intracerebral hemorrhage: from bench to clinical trials. Stroke 40:S90-91. https://doi.org/10.1161/strokeaha.108.533125 
  35. Crapper McLachlan DR, Dalton AJ, Kruck TP, Bell MY, Smith WL, Kalow W, Andrews DF (1991) Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet 337:1304-1308. https://doi.org/10.1016/0140-6736(91)92978-b 
  36. Martin-Sanchez D, Gallegos-Villalobos A, Fontecha-Barriuso M, Carrasco S, Sanchez-Nino MD, Lopez-Hernandez FJ, Ruiz-Ortega M, Egido J, Ortiz A, Sanz AB (2017) Deferasirox-induced iron depletion promotes BclxL downregulation and death of proximal tubular cells. Sci Rep 7:41510. https://doi.org/10.1038/srep41510