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Erschienen in: NeuroMolecular Medicine 2/2019

02.01.2019 | Review Paper

The Emerging Roles of Ferroptosis in Huntington’s Disease

verfasst von: Yajing Mi, Xingchun Gao, Hao Xu, Yuanyuan Cui, Yuelin Zhang, Xingchun Gou

Erschienen in: NeuroMolecular Medicine | Ausgabe 2/2019

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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.
Literatur
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.CrossRef 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.CrossRef
Zurück zum Zitat 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.CrossRef 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.CrossRef
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
Zurück zum Zitat Girotti, A. W. (1998). Lipid hydroperoxide generation, turnover, and effector action in biological systems. Journal of Lipid Research, 39(8), 1529–1542.PubMed Girotti, A. W. (1998). Lipid hydroperoxide generation, turnover, and effector action in biological systems. Journal of Lipid Research, 39(8), 1529–1542.PubMed
Zurück zum Zitat 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.CrossRef 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.CrossRef
Zurück zum Zitat 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.CrossRef 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.CrossRef
Zurück zum Zitat 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.CrossRef 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.CrossRef
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
Zurück zum Zitat 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.CrossRef 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.CrossRef
Zurück zum Zitat 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.CrossRef 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.CrossRef
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
Zurück zum Zitat 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.CrossRef 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.CrossRef
Zurück zum Zitat 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.CrossRef 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.CrossRef
Zurück zum Zitat 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.CrossRef 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.CrossRef
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
Zurück zum Zitat Vonsattel, J. P., & DiFiglia, M. (1998). Huntington disease. Journal of Neuropathology & Experimental Neurology, 57(5), 369–384.CrossRef Vonsattel, J. P., & DiFiglia, M. (1998). Huntington disease. Journal of Neuropathology & Experimental Neurology, 57(5), 369–384.CrossRef
Zurück zum Zitat 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.CrossRef 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.CrossRef
Metadaten
Titel
The Emerging Roles of Ferroptosis in Huntington’s Disease
verfasst von
Yajing Mi
Xingchun Gao
Hao Xu
Yuanyuan Cui
Yuelin Zhang
Xingchun Gou
Publikationsdatum
02.01.2019
Verlag
Springer US
Erschienen in
NeuroMolecular Medicine / Ausgabe 2/2019
Print ISSN: 1535-1084
Elektronische ISSN: 1559-1174
DOI
https://doi.org/10.1007/s12017-018-8518-6

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