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.
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Dixon, S. J. (2017). Ferroptosis: Bug or feature? Immunological Reviews, 277(1), 150–157. https://doi.org/10.1111/imr.12533.
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.
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.
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.
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.
Girotti, A. W. (1998). Lipid hydroperoxide generation, turnover, and effector action in biological systems. Journal of Lipid Research, 39(8), 1529–1542.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Vonsattel, J. P., & DiFiglia, M. (1998). Huntington disease. Journal of Neuropathology & Experimental Neurology, 57(5), 369–384.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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Mi, Y., Gao, X., Xu, H. et al. The Emerging Roles of Ferroptosis in Huntington’s Disease. Neuromol Med 21, 110–119 (2019). https://doi.org/10.1007/s12017-018-8518-6
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DOI: https://doi.org/10.1007/s12017-018-8518-6