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The Emerging Roles of Ferroptosis in Huntington’s Disease

  • Yajing Mi
  • Xingchun Gao
  • Hao Xu
  • Yuanyuan Cui
  • Yuelin ZhangEmail author
  • Xingchun GouEmail author
Review Paper
  • 214 Downloads

Abstract

Huntington’s disease (HD) is an autosomal dominant and fatal neurodegenerative disorder, which is caused by an abnormal CAG repeat in the huntingtin gene. Despite its well-defined genetic origin, the molecular mechanisms of neuronal death are unclear yet, thus there are no effective strategies to block or postpone the process of HD. Ferroptosis, a recently identified iron-dependent cell death, attracts considerable attention due to its putative involvement in neurodegenerative diseases. Accumulative data suggest that ferroptosis is very likely to participate in HD, and inhibition of the molecules and signaling pathways involved in ferroptosis can significantly eliminate the symptoms and pathology of HD. This review first describes evidence for the close relevance of ferroptosis and HD in patients and mouse models, then summarizes advances for the mechanisms of ferroptosis involved in HD, finally outlines some therapeutic strategies targeted ferroptosis. Comprehensive understanding of the emerging roles of ferroptosis in the occurrence of HD will help us to explore effective therapies for slowing the progression of this disease.

Keywords

Huntington’s disease Ferroptosis Mutant Huntingtin Lipid peroxidation Iron accumulation 

Notes

Acknowledgements

This work was supported by National Natural Science Foundation of China (81873740, 81471415, 81500063, 31600951, 81801088), Natural Science Basic Research Plan in Shaanxi Province of China (2017JM8086, 2017JQ8048), The Leading Disciplines Development Government Foundation of Shaanxi, and Xi’an Medical University’s key disciplines of molecular immunology.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. Abdalkader, M., Lampinen, R., Kanninen, K. M., Malm, T. M., & Liddell, J. R. (2018). Targeting Nrf2 to suppress ferroptosis and mitochondrial dysfunction in neurodegeneration. Frontiers in Neuroscience, 12, 466.  https://doi.org/10.3389/fnins.2018.00466.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Angeli, J. P. F., Shah, R., Pratt, D. A., & Conrad, M. (2017). Ferroptosis inhibition: Mechanisms and opportunities. Trends in Pharmacological Sciences, 38(5), 489–498.  https://doi.org/10.1016/j.tips.2017.02.005.CrossRefPubMedGoogle Scholar
  3. Ayala-Pena, S. (2013). Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis. Free Radical Biology and Medicine, 62, 102–110.  https://doi.org/10.1016/j.freeradbiomed.2013.04.017.CrossRefPubMedGoogle Scholar
  4. Baird, L., & Dinkova-Kostova, A. T. (2011). The cytoprotective role of the Keap1-Nrf2 pathway. Archives of Toxicology, 85(4), 241–272.  https://doi.org/10.1007/s00204-011-0674-5.CrossRefPubMedGoogle Scholar
  5. Barbiroli, B., Frassineti, C., Martinelli, P., Iotti, S., Lodi, R., Cortelli, P., & Montagna, P. (1997). Coenzyme Q10 improves mitochondrial respiration in patients with mitochondrial cytopathies. An in vivo study on brain and skeletal muscle by phosphorous magnetic resonance spectroscopy. Cellular and Molecular Biology (Noisy-le-grand), 43(5), 741–749.Google Scholar
  6. Bartzokis, G., Lu, P. H., Tishler, T. A., Fong, S. M., Oluwadara, B., Finn, J. P.,… Perlman, S. (2007). Myelin breakdown and iron changes in Huntington’s disease: Pathogenesis and treatment implications. Neurochemical Research, 32(10), 1655–1664.  https://doi.org/10.1007/s11064-007-9352-7.CrossRefPubMedGoogle Scholar
  7. Bradford, J., Shin, J. Y., Roberts, M., Wang, C. E., Sheng, G., Li, S., & Li, X. J. (2010). Mutant huntingtin in glial cells exacerbates neurological symptoms of Huntington disease mice. Journal of Biological Chemistry, 285(14), 10653–10661.  https://doi.org/10.1074/jbc.M109.083287.CrossRefPubMedGoogle Scholar
  8. Browne, S. E., & Beal, M. F. (2006). Oxidative damage in Huntington’s disease pathogenesis. Antioxidants & Redox Signaling, 8(11–12), 2061–2073.  https://doi.org/10.1089/ars.2006.8.2061.CrossRefGoogle Scholar
  9. Cao, J. Y., & Dixon, S. J. (2016). Mechanisms of ferroptosis. Cellular and Molecular Life Sciences, 73(11–12), 2195–2209.  https://doi.org/10.1007/s00018-016-2194-1.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cardoso, B. R., Hare, D. J., Bush, A. I., & Roberts, B. R. (2017). Glutathione peroxidase 4: A new player in neurodegeneration? Molecular Psychiatry, 22(3), 328–335.  https://doi.org/10.1038/mp.2016.196.CrossRefPubMedGoogle Scholar
  11. Cheah, J. H., Kim, S. F., Hester, L. D., Clancy, K. W., Patterson, S. E. 3rd, Papadopoulos, V., & Snyder, S. H. (2006). NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1. Neuron, 51(4), 431–440.  https://doi.org/10.1016/j.neuron.2006.07.011.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Chen, J., Marks, E., Lai, B., Zhang, Z., Duce, J. A., Lam, L. Q., Volitakis, I., Bush, A. I., Hersch, S., & Fox, J. H. (2013). Iron accumulates in Huntington’s disease neurons: Protection by deferoxamine. PLoS ONE, 8(10), e77023.  https://doi.org/10.1371/journal.pone.0077023.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Chen, L., Hambright, W. S., Na, R., & Ran, Q. (2015). Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. Journal of Biological Chemistry, 290(47), 28097–28106.  https://doi.org/10.1074/jbc.M115.680090.CrossRefPubMedGoogle Scholar
  14. Cheng, S. Y., Wang, S. C., Lei, M., Wang, Z., & Xiong, K. (2018). Regulatory role of calpain in neuronal death. Neural Regeneration Research, 13(3), 556–562.  https://doi.org/10.4103/1673-5374.228762.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Choi, B. R., Bang, S., Chen, Y., Cheah, J. H., & Kim, S. F. (2013). PKA modulates iron trafficking in the striatum via small GTPase. Rhes. Neuroscience, 253, 214–220.  https://doi.org/10.1016/j.neuroscience.2013.08.043.CrossRefPubMedGoogle Scholar
  16. Choo, Y. S., Johnson, G. V., MacDonald, M., Detloff, P. J., & Lesort, M. (2004). Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Human Molecular Genetics, 13(14), 1407–1420.CrossRefGoogle Scholar
  17. Conrad, M., Kagan, V. E., Bayir, H., Pagnussat, G. C., Head, B., Traber, M. G., & Stockwell, B. R. (2018). Regulation of lipid peroxidation and ferroptosis in diverse species. Genes & Development, 32(9–10), 602–619.  https://doi.org/10.1101/gad.314674.118.CrossRefGoogle Scholar
  18. Crotti, A., Benner, C., Kerman, B. E., Gosselin, D., Lagier-Tourenne, C., Zuccato, C., Cattaneo, E., Gage, F. H., Cleveland, D. W., & Glass, C. K. (2014). Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nature Neuroscience, 17(4), 513–521.  https://doi.org/10.1038/nn.3668.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Cui, L., Jeong, H., Borovecki, F., Parkhurst, C. N., Tanese, N., & Krainc, D. (2006). Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell, 127(1), 59–69.  https://doi.org/10.1016/j.cell.2006.09.015.CrossRefPubMedGoogle Scholar
  20. Deas, E., Cremades, N., Angelova, P. R., Ludtmann, M. H., Yao, Z., Chen, S.,… Abramov, A. Y. (2016). Alpha-synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson’s Disease. Antioxidants & Redox Signaling, 24(7), 376–391.  https://doi.org/10.1089/ars.2015.6343.CrossRefGoogle Scholar
  21. Dinkova-Kostova, A. T., Kostov, R. V., & Kazantsev, A. G. (2018). The role of Nrf2 signaling in counteracting neurodegenerative diseases. FEBS Journal.  https://doi.org/10.1111/febs.14379.CrossRefPubMedGoogle Scholar
  22. Dixon, S. J. (2017). Ferroptosis: Bug or feature? Immunological Reviews, 277(1), 150–157.  https://doi.org/10.1111/imr.12533.CrossRefPubMedGoogle Scholar
  23. Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E.,…, Stockwell, B. R. (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.CrossRefPubMedPubMedCentralGoogle Scholar
  24. East, D. A., Fagiani, F., Crosby, J., Georgakopoulos, N. D., Bertrand, H., Schaap, M.,… Campanella, M. (2014). PMI: A DeltaPsim independent pharmacological regulator of mitophagy. Chemistry & Biology, 21(11), 1585–1596.  https://doi.org/10.1016/j.chembiol.2014.09.019.CrossRefGoogle Scholar
  25. Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J.,… Conrad, M. (2014). Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology, 16(12), 1180–1191.  https://doi.org/10.1038/ncb3064.CrossRefPubMedGoogle Scholar
  26. Gerwyn, M., & Maes, M. (2017). Mechanisms explaining muscle fatigue and muscle pain in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A review of recent findings. Current Rheumatology Reports, 19(1), 1.  https://doi.org/10.1007/s11926-017-0628-x.CrossRefPubMedGoogle Scholar
  27. Girotti, A. W. (1998). Lipid hydroperoxide generation, turnover, and effector action in biological systems. Journal of Lipid Research, 39(8), 1529–1542.PubMedGoogle Scholar
  28. Grolez, G., Moreau, C., Sablonniere, B., Garcon, G., Devedjian, J. C., Meguig, S.,… Devos, D. (2015). Ceruloplasmin activity and iron chelation treatment of patients with Parkinson’s disease. BMC Neurology, 15, 74.  https://doi.org/10.1186/s12883-015-0331-3.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Grondin, R., Kaytor, M. D., Ai, Y., Nelson, P. T., Thakker, D. R., Heisel, J.,… Kaemmerer, W. F. (2012). Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain, 135(Pt 4), 1197–1209.  https://doi.org/10.1093/brain/awr333.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Guo, X., Disatnik, M. H., Monbureau, M., Shamloo, M., Mochly-Rosen, D., & Qi, X. (2013). Inhibition of mitochondrial fragmentation diminishes Huntington’s disease-associated neurodegeneration. The Journal of Clinical Investigation, 123(12), 5371–5388.  https://doi.org/10.1172/JCI70911.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Ho, L. W., Brown, R., Maxwell, M., Wyttenbach, A., & Rubinsztein, D. C. (2001). Wild type Huntingtin reduces the cellular toxicity of mutant Huntingtin in mammalian cell models of Huntington’s disease. Journal of Medical Genetics, 38(7), 450–452.CrossRefGoogle Scholar
  32. Ingold, I., Berndt, C., Schmitt, S., Doll, S., Poschmann, G., Buday, K.,… Conrad, M. (2018). Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell, 172(3), 409–422 e421.  https://doi.org/10.1016/j.cell.2017.11.048.CrossRefPubMedGoogle Scholar
  33. Jana, N. R., Zemskov, E. A., Wang, G., & Nukina, N. (2001). Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Human Molecular Genetics, 10(10), 1049–1059.CrossRefGoogle Scholar
  34. Jimenez-Sanchez, M., Licitra, F., Underwood, B. R., & Rubinsztein, D. C. (2017) Huntington’s disease: Mechanisms of pathogenesis and therapeutic strategies. Cold Spring Harbor Perspectives in Medicine.  https://doi.org/10.1101/cshperspect.a024240.CrossRefPubMedGoogle Scholar
  35. Johnson, W. M., Wilson-Delfosse, A. L., & Mieyal, J. J. (2012). Dysregulation of glutathione homeostasis in neurodegenerative diseases. Nutrients, 4(10), 1399–1440.  https://doi.org/10.3390/nu4101399.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Joshi, Y. B., Giannopoulos, P. F., & Pratico, D. (2015). The 12/15-lipoxygenase as an emerging therapeutic target for Alzheimer’s disease. Trends in Pharmacological Sciences, 36(3), 181–186.  https://doi.org/10.1016/j.tips.2015.01.005.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Kim, D. W., Hwang, I. K., Yoo, K. Y., Won, C. K., Moon, W. K., & Won, M. H. (2007). Coenzyme Q_{10} effects on manganese superoxide dismutase and glutathione peroxidase in the hairless mouse skin induced by ultraviolet B irradiation. Biofactors, 30(3), 139–147.CrossRefGoogle Scholar
  38. Klepac, N., Relja, M., Klepac, R., Hecimovic, S., Babic, T., & Trkulja, V. (2007). Oxidative stress parameters in plasma of Huntington’s disease patients, asymptomatic Huntington’s disease gene carriers and healthy subjects: A cross-sectional study. Journal of Neurology, 254(12), 1676–1683.  https://doi.org/10.1007/s00415-007-0611-y.CrossRefPubMedGoogle Scholar
  39. Kumar, P., Kalonia, H., & Kumar, A. (2010). Nitric oxide mechanism in the protective effect of antidepressants against 3-nitropropionic acid-induced cognitive deficit, glutathione and mitochondrial alterations in animal model of Huntington’s disease. Behavioural Pharmacology, 21(3), 217–230.CrossRefGoogle Scholar
  40. Kuo, K. H., & Mrkobrada, M. (2014). A systematic review and meta-analysis of deferiprone monotherapy and in combination with deferoxamine for reduction of iron overload in chronically transfused patients with beta-thalassemia. Hemoglobin, 38(6), 409–421.  https://doi.org/10.3109/03630269.2014.965781.CrossRefPubMedGoogle Scholar
  41. Kwan, W., Trager, U., Davalos, D., Chou, A., Bouchard, J., Andre, R.,… Muchowski, P. J. (2012). Mutant huntingtin impairs immune cell migration in Huntington disease. The Journal of Clinical Investigation, 122(12), 4737–4747.  https://doi.org/10.1172/JCI64484.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Leavitt, B. R., van Raamsdonk, J. M., Shehadeh, J., Fernandes, H., Murphy, Z.,… Hayden, M. R. (2006). Wild-type huntingtin protects neurons from excitotoxicity. Journal of Neurochemistry, 96(4), 1121–1129.  https://doi.org/10.1111/j.1471-4159.2005.03605.x.CrossRefPubMedGoogle Scholar
  43. Lee, J., Kosaras, B., Del Signore, S. J., Cormier, K., McKee, A., Ratan, R. R., Kowall, N. W., & Ryu, H. (2011). Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington’s disease mice. Acta Neuropathologica, 121(4), 487–498.  https://doi.org/10.1007/s00401-010-0788-5.CrossRefPubMedGoogle Scholar
  44. MacDonald, M. E., Ambrose, C. M., Duyao, M. P., Myers, R. H., Lin, C., Srinidhi, L.,... MacFarlane, H. (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cell, 72(6), 971–983.CrossRefGoogle Scholar
  45. Maiorino, M., Conrad, M., & Ursini, F. (2017). GPx4, lipid peroxidation, and cell death: Discoveries, rediscoveries, and open issues. Antioxidants & Redox Signaling.  https://doi.org/10.1089/ars.2017.7115.CrossRefGoogle Scholar
  46. Majumder, P., Raychaudhuri, S., Chattopadhyay, B., & Bhattacharyya, N. P. (2007). Increased caspase-2, calpain activations and decreased mitochondrial complex II activity in cells expressing exogenous huntingtin exon 1 containing CAG repeat in the pathogenic range. Cellular and Molecular Neurobiology, 27(8), 1127–1145.  https://doi.org/10.1007/s10571-007-9220-7.CrossRefPubMedGoogle Scholar
  47. Mao, Z., Choo, Y. S., & Lesort, M. (2006). Cystamine and cysteamine prevent 3-NP-induced mitochondrial depolarization of Huntington’s disease knock-in striatal cells. European Journal of Neuroscience, 23(7), 1701–1710.  https://doi.org/10.1111/j.1460-9568.2006.04686.x.CrossRefPubMedGoogle Scholar
  48. Matthews, R. T., Yang, L., Browne, S., Baik, M., & Beal, M. F. (1998). Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proceedings of the National Academy of Sciences, 95(15), 8892–8897.CrossRefGoogle Scholar
  49. McBride, J. L., Pitzer, M. R., Boudreau, R. L., Dufour, B., Hobbs, T., Ojeda, S. R., & Davidson, B. L. (2011). Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease. Molecular Therapy, 19(12), 2152–2162.  https://doi.org/10.1038/mt.2011.219.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Mealer, R. G., Murray, A. J., Shahani, N., Subramaniam, S., & Snyder, S. H. (2014). Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy. Journal of Biological Chemistry, 289(6), 3547–3554.  https://doi.org/10.1074/jbc.M113.536912.CrossRefPubMedGoogle Scholar
  51. Merry, T. L., & Ristow, M. (2016). Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) mediates exercise-induced mitochondrial biogenesis and the anti-oxidant response in mice. The Journal of Physiology, 594(18), 5195–5207.  https://doi.org/10.1113/JP271957.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Morris, G., Anderson, G., Berk, M., & Maes, M. (2013). Coenzyme Q10 depletion in medical and neuropsychiatric disorders: Potential repercussions and therapeutic implications. Molecular Neurobiology, 48(3), 883–903.  https://doi.org/10.1007/s12035-013-8477-8.CrossRefPubMedGoogle Scholar
  53. Morris, G., Berk, M., Galecki, P., Walder, K., & Maes, M. (2016). The neuro-immune pathophysiology of central and peripheral fatigue in systemic immune-inflammatory and neuro-immune diseases. Molecular Neurobiology, 53(2), 1195–1219.  https://doi.org/10.1007/s12035-015-9090-9.CrossRefPubMedGoogle Scholar
  54. Muller, M., & Leavitt, B. R. (2014). Iron dysregulation in Huntington’s disease. Journal of Neurochemistry, 130(3), 328–350.  https://doi.org/10.1111/jnc.12739.CrossRefPubMedGoogle Scholar
  55. Orr, A. L., Li, S., Wang, C. E., Li, H., Wang, J., Rong, J.,… Li, X. J. (2008). N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. Journal of Neuroscience, 28(11), 2783–2792.  https://doi.org/10.1523/JNEUROSCI.0106-08.2008.CrossRefPubMedGoogle Scholar
  56. Paul, B. D., Sbodio, J. I., Xu, R., Vandiver, M. S., Cha, J. Y., Snowman, A. M., & Snyder, S. H. (2014). Cystathionine gamma-lyase deficiency mediates neurodegeneration in Huntington’s disease. Nature, 509(7498), 96–100.  https://doi.org/10.1038/nature13136.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Prasad, K. N., & Bondy, S. C. (2016). Inhibition of early biochemical defects in prodromal Huntington’s Disease by simultaneous activation of Nrf2 and elevation of multiple micronutrients. Current Aging Science, 9(1), 61–70.CrossRefGoogle Scholar
  58. Pringsheim, T., Wiltshire, K., Day, L., Dykeman, J., Steeves, T., & Jette, N. (2012). The incidence and prevalence of Huntington’s disease: A systematic review and meta-analysis. Movement Disorders, 27(9), 1083–1091.  https://doi.org/10.1002/mds.25075.CrossRefPubMedGoogle Scholar
  59. Proneth, B., & Conrad, M. (2018). Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death & Differentiation.  https://doi.org/10.1038/s41418-018-0173-9.CrossRefGoogle Scholar
  60. Quinti, L., Casale, M., Moniot, S., Pais, T. F., Van Kanegan, M. J.,… Kazantsev, A. G. (2016). SIRT2- and NRF2-targeting thiazole-containing compound with therapeutic activity in Huntington’s Disease models. Cell Chemical Biology, 23(7), 849–861.  https://doi.org/10.1016/j.chembiol.2016.05.015.CrossRefPubMedGoogle Scholar
  61. Quinti, L., Dayalan Naidu, S., Trager, U., Chen, X., Kegel-Gleason, K., Lleres, D.,… Kazantsev, A. G. (2017). KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington’s disease patients. Proceedings of the National Academy of Sciences, 114(23), E4676–E4685.  https://doi.org/10.1073/pnas.1614943114.CrossRefGoogle Scholar
  62. Ran, Q., Liang, H., Gu, M., Qi, W., Walter, C. A., Roberts, L. J. 2nd,… Van Remmen, H. (2004). Transgenic mice overexpressing glutathione peroxidase 4 are protected against oxidative stress-induced apoptosis. Journal of Biological Chemistry, 279(53), 55137–55146.  https://doi.org/10.1074/jbc.M410387200.CrossRefPubMedGoogle Scholar
  63. Reddy, P. H., Reddy, T. P., Manczak, M., Calkins, M. J., Shirendeb, U., & Mao, P. (2011). Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases. Brain Research Reviews, 67(1–2), 103–118.  https://doi.org/10.1016/j.brainresrev.2010.11.004.CrossRefPubMedGoogle Scholar
  64. Reddy, P. H., & Shirendeb, U. P. (2012). Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington’s disease. Biochimica et Biophysica Acta, 1822(2), 101–110.  https://doi.org/10.1016/j.bbadis.2011.10.016.CrossRefPubMedGoogle Scholar
  65. Rosas, H. D., Chen, Y. I., Doros, G., Salat, D. H., Chen, N. K., Kwong, K. K.,… Hersch, S. M. (2012). Alterations in brain transition metals in Huntington disease: An evolving and intricate story. Archives of Neurology, 69(7), 887–893.  https://doi.org/10.1001/archneurol.2011.2945.CrossRefPubMedPubMedCentralGoogle Scholar
  66. Rosenblatt, A., Liang, K. Y., Zhou, H., Abbott, M. H., Gourley, L. M., Margolis, R. L., Brandt, J., & Ross, C. A. (2006). The association of CAG repeat length with clinical progression in Huntington disease. Neurology, 66(7), 1016–1020.  https://doi.org/10.1212/01.wnl.0000204230.16619.d9.CrossRefPubMedGoogle Scholar
  67. Ross, C. A., & Tabrizi, S. J. (2011). Huntington’s disease: From molecular pathogenesis to clinical treatment. The Lancet Neurology, 10(1), 83–98.  https://doi.org/10.1016/S1474-4422(10)70245-3.CrossRefPubMedGoogle Scholar
  68. Roze, E., Saudou, F., & Caboche, J. (2008). Pathophysiology of Huntington’s disease: From huntingtin functions to potential treatments. Current Opinion in Neurology, 21(4), 497–503.  https://doi.org/10.1097/WCO.0b013e328304b692.CrossRefPubMedGoogle Scholar
  69. Sandhir, R., Sood, A., Mehrotra, A., & Kamboj, S. S. (2012). N-Acetylcysteine reverses mitochondrial dysfunctions and behavioral abnormalities in 3-nitropropionic acid-induced Huntington’s disease. Neurodegenerative Diseases, 9(3), 145–157.  https://doi.org/10.1159/000334273.CrossRefPubMedGoogle Scholar
  70. Seiler, A., Schneider, M., Forster, H., Roth, S., Wirth, E. K., Culmsee, C.,… Conrad, M. (2008). Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metabolism, 8(3), 237–248.  https://doi.org/10.1016/j.cmet.2008.07.005.CrossRefPubMedGoogle Scholar
  71. Shirendeb, U. P., Calkins, M. J., Manczak, M., Anekonda, V., Dufour, B., McBride, J. L., Mao, P., & Reddy, P. H. (2012). Mutant huntingtin’s interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington’s disease. Human Molecular Genetics, 21(2), 406–420.  https://doi.org/10.1093/hmg/ddr475.CrossRefPubMedGoogle Scholar
  72. Simmons, D. A., Casale, M., Alcon, B., Pham, N., Narayan, N., & Lynch, G. (2007). Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington’s disease. Glia, 55(10), 1074–1084.  https://doi.org/10.1002/glia.20526.CrossRefPubMedGoogle Scholar
  73. Skouta, R., Dixon, S. J., Wang, J., Dunn, D. E., Orman, M., Shimada, K.,… Stockwell, B. R. (2014). Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. Journal of the American Chemical Society, 136(12), 4551–4556.  https://doi.org/10.1021/ja411006a.CrossRefPubMedPubMedCentralGoogle Scholar
  74. Sripetchwandee, J., Wongjaikam, S., Krintratun, W., Chattipakorn, N., & Chattipakorn, S. C. (2016). A combination of an iron chelator with an antioxidant effectively diminishes the dendritic loss, tau-hyperphosphorylation, amyloids-beta accumulation and brain mitochondrial dynamic disruption in rats with chronic iron-overload. Neuroscience, 332, 191–202.  https://doi.org/10.1016/j.neuroscience.2016.07.003.CrossRefPubMedGoogle Scholar
  75. Stack, C., Ho, D., Wille, E., Calingasan, N. Y., Williams, C., Liby, K., Sporn, M., Dumont, M., & Beal, M. F. (2010). Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington’s disease. Free Radical Biology and Medicine, 49(2), 147–158.  https://doi.org/10.1016/j.freeradbiomed.2010.03.017.CrossRefPubMedGoogle Scholar
  76. Subramaniam, S., Sixt, K. M., Barrow, R., & Snyder, S. H. (2009). Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science, 324(5932), 1327–1330.  https://doi.org/10.1126/science.1172871.CrossRefPubMedPubMedCentralGoogle Scholar
  77. Turmaine, M., Raza, A., Mahal, A., Mangiarini, L., Bates, G. P., & Davies, S. W. (2000). Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington’s disease. Proceedings of the National Academy of Sciences, 97(14), 8093–8097.  https://doi.org/10.1073/pnas.110078997.CrossRefGoogle Scholar
  78. van Bergen, J. M., Hua, J., Unschuld, P. G., Lim, I. A., Jones, C. K., Margolis, R. L.,… Li, X. (2016). Quantitative susceptibility mapping suggests altered brain iron in premanifest huntington disease. AJNR American Journal of Neuroradiology, 37(5), 789–796.  https://doi.org/10.3174/ajnr.A4617.CrossRefPubMedGoogle Scholar
  79. Varela-Lopez, A., Giampieri, F., Battino, M., & Quiles, J. L. (2016). Coenzyme Q and its role in the dietary therapy against aging. Molecules, 21(3), 373.  https://doi.org/10.3390/molecules21030373.CrossRefPubMedPubMedCentralGoogle Scholar
  80. Vargiu, P., De Abajo, R., Garcia-Ranea, J. A., Valencia, A., Santisteban, P., Crespo, P., & Bernal, J. (2004). The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors. Oncogene, 23(2), 559–568.  https://doi.org/10.1038/sj.onc.1207161.CrossRefPubMedGoogle Scholar
  81. Velusamy, T., Panneerselvam, A. S., Purushottam, M., Anusuyadevi, M., Pal, P. K., Jain, S., Essa, M. M., Guillemin, G. J., & Kandasamy, M. (2017). Protective effect of antioxidants on neuronal dysfunction and plasticity in Huntington’s Disease. Oxidative Medicine and Cellular Longevity, 2017, 3279061.  https://doi.org/10.1155/2017/3279061.CrossRefPubMedPubMedCentralGoogle Scholar
  82. Vonsattel, J. P., & DiFiglia, M. (1998). Huntington disease. Journal of Neuropathology & Experimental Neurology, 57(5), 369–384.CrossRefGoogle Scholar
  83. Wexler, N. S., Lorimer, J., Porter, J., Gomez, F., Moskowitz, C., Shackell, E.,… Landwehrmeyer, B. (2004). Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proceedings of the National Academy of Sciences, 101(10), 3498–3503.  https://doi.org/10.1073/pnas.0308679101.CrossRefGoogle Scholar
  84. Wild, E., Magnusson, A., Lahiri, N., Krus, U., Orth, M., Tabrizi, S. J., & Bjorkqvist, M. (2011). Abnormal peripheral chemokine profile in Huntington’s disease. PLoS Currents, 3, RRN1231.  https://doi.org/10.1371/currents.RRN1231.CrossRefPubMedPubMedCentralGoogle Scholar
  85. Wongjaikam, S., Kumfu, S., Khamseekaew, J., Sripetchwandee, J., Srichairatanakool, S., Fucharoen, S., Chattipakorn, S. C., & Chattipakorn, N. (2016). Combined iron chelator and antioxidant exerted greater efficacy on cardioprotection than monotherapy in iron-overloaded rats. PLoS ONE, 11(7), e0159414.  https://doi.org/10.1371/journal.pone.0159414.CrossRefPubMedPubMedCentralGoogle Scholar
  86. Wu, C., Zhao, W., Yu, J., Li, S., Lin, L., & Chen, X. (2018). Induction of ferroptosis and mitochondrial dysfunction by oxidative stress in PC12 cells. Scientific Reports, 8(1), 574.  https://doi.org/10.1038/s41598-017-18935-1.CrossRefPubMedPubMedCentralGoogle Scholar
  87. Xie, Y., Hou, W., Song, X., Yu, Y., Huang, J., Sun, X., Kang, R., & Tang, D. (2016). Ferroptosis: Process and function. Cell Death and Differentiation, 23(3), 369–379.  https://doi.org/10.1038/cdd.2015.158.CrossRefPubMedPubMedCentralGoogle Scholar
  88. Yagoda, N., von Rechenberg, M., Zaganjor, E., Bauer, A. J., Yang, W. S., Fridman, D. J.,… Stockwell, B. R. (2007). RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature, 447(7146), 864–868.  https://doi.org/10.1038/nature05859.CrossRefPubMedPubMedCentralGoogle Scholar
  89. Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018). The KEAP1-NRF2 system: A thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiological Reviews, 98(3), 1169–1203.  https://doi.org/10.1152/physrev.00023.2017.CrossRefPubMedGoogle Scholar
  90. Yang, W. S., SriRamaratnam, R., Welsch, M. E., Shimada, K., Skouta, R., Viswanathan, V. S.,… Stockwell, B. R. (2014). Regulation of ferroptotic cancer cell death by GPX4. Cell, 156(1–2), 317–331.  https://doi.org/10.1016/j.cell.2013.12.010.CrossRefPubMedPubMedCentralGoogle Scholar
  91. Yang, W. S., & Stockwell, B. R. (2008). Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chemistry & Biology, 15(3), 234–245.  https://doi.org/10.1016/j.chembiol.2008.02.010.CrossRefGoogle Scholar
  92. Yang, W. S., & Stockwell, B. R. (2016). Ferroptosis: Death by lipid peroxidation. Trends in Cell Biology, 26(3), 165–176.  https://doi.org/10.1016/j.tcb.2015.10.014.CrossRefPubMedGoogle Scholar
  93. Yano, H., Baranov, S. V., Baranova, O. V., Kim, J., Pan, Y., Yablonska, S.,… Friedlander, R. M. (2014). Inhibition of mitochondrial protein import by mutant huntingtin. Nature Neuroscience, 17(6), 822–831.  https://doi.org/10.1038/nn.3721.CrossRefPubMedPubMedCentralGoogle Scholar
  94. Zhang, Y., Leavitt, B. R., van Raamsdonk, J. M., Dragatsis, I., Goldowitz, D., MacDonald, M. E., Hayden, M. R., & Friedlander, R. M. (2006). Huntingtin inhibits caspase-3 activation. The EMBO Journal, 25(24), 5896–5906.  https://doi.org/10.1038/sj.emboj.7601445.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Shaanxi Key Laboratory of Brain Disorders, and Department of Basic MedicineXi’an Medical UniversityXi’anChina

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