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題名 腦中缺少GPx4引起細胞死亡之研究
The study of GPx4-deficiency induced cell death in the brain
作者 吳玥彤
Wu, Yue-Tong
貢獻者 陳紹寬
Chen, Shau-Kwaun
吳玥彤
Wu, Yue-Tong
關鍵詞 鐵依賴性細胞死亡
穀胱甘肽過氧化物酶4
發炎
細胞凋亡
細胞壞死
細胞焦亡
Ferroptosis
Glutathione peroxidase 4
inflammation
Apoptosis
Necroptosis
Pyroptosis
日期 2023
上傳時間 1-Sep-2023 16:38:37 (UTC+8)
摘要 鐵依賴性死亡（Ferroptosis）被認為是程序性細胞死亡（PCD）的一種新形式，其特徵包括鐵代謝紊亂、脂質過氧化物積累和氧化應激增加等等，近年來發現其參與多種神經退行性疾病的發病機制，如阿茲海默病、帕金森氏症等，並提及在患者腦中發現了細胞發炎和鐵依賴性死亡的特徵，而穀胱甘肽過氧化物酶4（GPx4）功能的喪失被認為是導致神經系統疾病中細胞發生鐵依賴性死亡的主要因素之一，但對於如何造成上述疾病中神經細胞大量死亡的病理機制仍不清楚。本研究旨在探討 GPx4 基因的敲除是否會引發鐵依賴性死亡及誘發神經炎症，並將進一步探討在其他發炎相關的細胞死亡中的影響。我們使用Gad2Cre/GPx4基因剔除鼠來研究Gpx4基因的剔除在腦中導致的細胞死亡。我們所觀察的所有突變鼠在P7開始可觀察到體重下降等表型，並會在P14前死亡，死亡前表現嚴重的活動下降及痙攣，顯示突變鼠神經系統功能異常。以外，在尼氏染色的結果中突變鼠的大腦前額葉皮層與小腦的細胞組織明顯受到破壞、小腦細胞數量減少及分子層變薄，表明腦部結構異常。通過檢測結構異常的腦區變化，發現突變體小腦中柏金氏細胞及顆粒細胞數量減少、前額葉皮質層及小腦中促發炎因子上調和小膠質細胞形態改變，顯示GABA能神經元死亡的發生可能引發周圍細胞死亡並伴隨發炎反應。實驗發現4-HNe水平的增加並不局限於γ-氨基丁酸能的柏金氏神經元，其在顆粒層也有發現，這表明鐵依賴性細胞死亡訊號可傳遞到其他細胞。最後，我們還研究了發炎可能誘導的其他類型的調節性細胞死亡，包括細胞焦亡和壞死。有趣的是，細胞焦亡途徑在柏金氏神經元和顆粒細胞中得到了促進，而細胞壞死途徑在突變鼠中似乎受到了抑制，我們的研究结果表明GPx4 消融會觸發柏金氏神經元的多種死亡途徑，並向鄰近細胞釋放信號以調節細胞的存活或死亡，組織中複雜的細胞死亡調控網路可能是慢性發展疾病發病機制的關鍵訊息。
Ferroptosis is considered a novel form of programmed cell death (PCD), characterized by disorders of iron metabolism, accumulation of lipid peroxides, and increased oxidative stress, etc. In recent years, that ferroptosis is involved in the pathogenesis of various neurodegenerative diseases, such as Alzheimer`s disease, Parkinson`s disease. Previous studies suggested that features of cellular inflammation and Ferroptosis were found in the brains of patients, suggesting that glutathione peroxidase 4 (GPx4) plays an important role in intracellular antioxidant action. However, loss of GPx4 function is thought to be one of the factors contributing to the onset of ferroptosis in cells with neurodegenerative diseases, but the pathological mechanisms of how ferroptosis is involved in the disease remain unclear. The present study was designed to investigate whether ablation of Gpx4 gene triggers ferroptosis and its effect on neuroinflammation. Also, we will further investigate the roles of Gpx4 in the regulation of cell death, providing potential applications for the treatment of neurodegenerative diseases. Given this, we used Gad2Cre/GPx4 knockout mice to investigate the physiological functions of GPx4 in neuronal cells and whether it causes cell death. All of the mutants we observed had phenotypes such as weight loss starting at P7 and died before P14, showing severe decreased activity and seizure, suggesting that the mutation is a neurological abnormality. Furthermore, the results of Nissl staining revealed significant disruptions in the cellular organization of the prefrontal cortex and cerebellum in the brains of mutants, as well as a decreased cell count and a thinner molecular layer in the cerebellum. These findings indicate abnormal brain structure. Moreover, through the examination of structural abnormalities in the affected brain regions, we found reduced numbers of Purkinje cells and granule cells, upregulation of proinflammatory mediator, and the morphological changes of microglia in the prefrontal cortex and cerebellum of the mutants, indicating that the onset of GABAergic neuronal death may trigger peripheral cell death with a concomitant inflammatory response. The experimental finding that increased levels of 4-HNe were not limited to GABAergic Purkinje neurons, but were also found in the granular layer, suggests that iron apoptosis can be transmitted to other cells. Finally, the researchers also examined other types of regulatory cell death that may be induced by inflammation, including thermal apoptosis and necrosis. Interestingly, the thermoapoptotic pathway was promoted in Purkinje neurons and granule cells, whereas the necroptotic pathway appeared to be inhibited in mutants. Our findings suggest that Gpx4 deficiency triggers multiple death pathways in Purkinje neurons and releases signals to neighboring cells to regulate cell survival or death. The complex network of cell death regulation in tissues may be key information for the pathogenesis of chronic progressive diseases.
參考文獻 Alturki NA, McComb S, Ariana A, Rijal D, Korneluk RG, Sun SC, Alnemri E, Sad S (2018) Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis. Cell Death Dis 9:592.
Belaidi AA, Bush AI (2016) Iron neurochemistry in Alzheimer`s disease and Parkinson`s disease: targets for therapeutics. J Neurochem 139 Suppl 1:179-197.
Belaidi AA, Gunn AP, Wong BX, Ayton S, Appukuttan AT, Roberts BR, Duce JA, Bush AI (2018) Marked Age-Related Changes in Brain Iron Homeostasis in Amyloid Protein Precursor Knockout Mice. Neurotherapeutics 15:1055-1062.
Berg D, Youdim MB (2006) Role of iron in neurodegenerative disorders. Top Magn Reson Imaging 17:5-17.
Bjørklund G, Peana M, Maes M, Dadar M, Severin B (2021) The glutathione system in Parkinson`s disease and its progression. Neurosci Biobehav Rev 120:470-478.
Brigelius-Flohé R, Maiorino M (2013) Glutathione peroxidases. Biochim Biophys Acta 1830:3289-3303.
Buijs M, Doan NT, van Rooden S, Versluis MJ, van Lew B, Milles J, van der Grond J, van Buchem MA (2017) In vivo assessment of iron content of the cerebral cortex in healthy aging using 7-Tesla T2*-weighted phase imaging. Neurobiol Aging 53:20-26.
Chan ED, Riches DW (2001) IFN-gamma + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38(mapk) in a mouse macrophage cell line. Am J Physiol Cell Physiol 280:C441-450.
Chen K, Jiang X, Wu M, Cao X, Bao W, Zhu LQ (2021a) Ferroptosis, a Potential Therapeutic Target in Alzheimer`s Disease. Front Cell Dev Biol 9:704298.
Chen L, Hambright WS, Na R, Ran Q (2015) Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis. J Biol Chem 290:28097-28106.
Chen X, Comish PB, Tang D, Kang R (2021b) Characteristics and Biomarkers of Ferroptosis. Front Cell Dev Biol 9:637162.
Chen X, He WT, Hu L, Li J, Fang Y, Wang X, Xu X, Wang Z, Huang K, Han J (2016) Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res 26:1007-1020.
Cheng Y, Song Y, Chen H, Li Q, Gao Y, Lu G, Luo C (2021) Ferroptosis Mediated by Lipid Reactive Oxygen Species: A Possible Causal Link of Neuroinflammation to Neurological Disorders. Oxid Med Cell Longev 2021:5005136.
Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer`s disease transgenic mice. Neuron 30:665-676.
Christgen S, Tweedell RE, Kanneganti TD (2022) Programming inflammatory cell death for therapy. Pharmacol Ther 232:108010.
Conrad M (2009) Transgenic mouse models for the vital selenoenzymes cytosolic thioredoxin reductase, mitochondrial thioredoxin reductase and glutathione peroxidase 4. Biochim Biophys Acta 1790:1575-1585.
D`Souza CA, Heitman J (2001) Dismantling the Cryptococcus coat. Trends Microbiol 9:112-113.
Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F (1993) Glutathione peroxidase, glial cells and Parkinson`s disease. Neuroscience 52:1-6.
Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112-119.
Deponte M (2013) Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Biochim Biophys Acta 1830:3217-3266.
Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, Thomas AG, Gleason CE, Tatonetti NP, Slusher BS, Stockwell BR (2014) Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3:e02523.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, 3rd, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060-1072.
Do Van B, Gouel F, Jonneaux A, Timmerman K, Gelé P, Pétrault M, Bastide M, Laloux C, Moreau C, Bordet R, Devos D, Devedjian JC (2016) Ferroptosis, a newly characterized form of cell death in Parkinson`s disease that is regulated by PKC. Neurobiol Dis 94:169-178.
Duan X, Liu X, Liu N, Huang Y, Jin Z, Zhang S, Ming Z, Chen H (2020) Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation. Cell Death Dis 11:134.
Esworthy RS, Doan K, Doroshow JH, Chu FF (1994) Cloning and sequencing of the cDNA encoding a human testis phospholipid hydroperoxide glutathione peroxidase. Gene 144:317-318.
Febbraro F, Andersen KJ, Sanchez-Guajardo V, Tentillier N, Romero-Ramos M (2013) Chronic intranasal deferoxamine ameliorates motor defects and pathology in the α-synuclein rAAV Parkinson`s model. Exp Neurol 247:45-58.
Federico A, Morgillo F, Tuccillo C, Ciardiello F, Loguercio C (2007) Chronic inflammation and oxidative stress in human carcinogenesis. Int J Cancer 121:2381-2386.
Ferguson LR, Karunasinghe N, Zhu S, Wang AH (2012) Selenium and its` role in the maintenance of genomic stability. Mutat Res 733:100-110.
Fine EJ, Ionita CC, Lohr L (2002) The history of the development of the cerebellar examination. Semin Neurol 22:375-384.
Fine JM, Baillargeon AM, Renner DB, Hoerster NS, Tokarev J, Colton S, Pelleg A, Andrews A, Sparley KA, Krogh KM, Frey WH, Hanson LR (2012) Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice. Exp Brain Res 219:381-390.
Fink SL, Cookson BT (2006) Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol 8:1812-1825.
Friedmann Angeli JP et al. (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16:1180-1191.
Gao P, Cao M, Jiang X, Wang X, Zhang G, Tang X, Yang C, Komuro I, Ge J, Li L, Zou Y (2023) Cannabinoid Receptor 2-Centric Molecular Feedback Loop Drives Necroptosis in Diabetic Heart Injuries. Circulation 147:158-174.
Grossi C, Francese S, Casini A, Rosi MC, Luccarini I, Fiorentini A, Gabbiani C, Messori L, Moneti G, Casamenti F (2009) Clioquinol decreases amyloid-beta burden and reduces working memory impairment in a transgenic mouse model of Alzheimer`s disease. J Alzheimers Dis 17:423-440.
Gu F, Chauhan V, Chauhan A (2015) Glutathione redox imbalance in brain disorders. Curr Opin Clin Nutr Metab Care 18:89-95.
Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, Tardivel A, Heuschling P, Dostert C (2015) NLRP3 Inflammasome Is Expressed and Functional in Mouse Brain Microglia but Not in Astrocytes. PLoS One 10:e0130624.
Haddad JJ, Harb HL (2005) L-gamma-Glutamyl-L-cysteinyl-glycine (glutathione; GSH) and GSH-related enzymes in the regulation of pro- and anti-inflammatory cytokines: a signaling transcriptional scenario for redox(y) immunologic sensor(s)? Mol Immunol 42:987-1014.
Hambright WS, Fonseca RS, Chen L, Na R, Ran Q (2017) Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol 12:8-17.
Haque ME, Akther M, Jakaria M, Kim IS, Azam S, Choi DK (2020) Targeting the microglial NLRP3 inflammasome and its role in Parkinson`s disease. Mov Disord 35:20-33.
Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson`s disease: a target for neuroprotection? Lancet Neurol 8:382-397.
Hu HL, Bennett N, Holton JL, Nolan CC, Lister T, Cavanagh JB, Ray DE (1999) Glutathione depletion increases brain susceptibility to m-dinitrobenzene neurotoxicity. Neurotoxicology 20:83-90.
Ingold I et al. (2018) Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell 172:409-422.e421.
Iskusnykh IY, Zakharova AA, Pathak D (2022) Glutathione in Brain Disorders and Aging. Molecules 27.
Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, Baer R, Gu W (2015) Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520:57-62.
Jiang X, Stockwell BR, Conrad M (2021) Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 22:266-282.
Kayagaki N et al. (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666-671.
Kim J, Byun JW, Choi I, Kim B, Jeong HK, Jou I, Joe E (2013) PINK1 Deficiency Enhances Inflammatory Cytokine Release from Acutely Prepared Brain Slices. Exp Neurobiol 22:38-44.
Kim K (2021) Glutathione in the Nervous System as a Potential Therapeutic Target to Control the Development and Progression of Amyotrophic Lateral Sclerosis. Antioxidants (Basel) 10.
Labrecque CL, Fuglestad B (2021) Electrostatic Drivers of GPx4 Interactions with Membrane, Lipids, and DNA. Biochemistry 60:2761-2772.
Labunskyy VM, Hatfield DL, Gladyshev VN (2014) Selenoproteins: molecular pathways and physiological roles. Physiol Rev 94:739-777.
Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, Sun B, Wang G (2020) Ferroptosis: past, present and future. Cell Death Dis 11:88.
Li J, Li M, Ge Y, Chen J, Ma J, Wang C, Sun M, Wang L, Yao S, Yao C (2022) β-amyloid protein induces mitophagy-dependent ferroptosis through the CD36/PINK/PARKIN pathway leading to blood-brain barrier destruction in Alzheimer`s disease. Cell Biosci 12:69.

Liddelow SA et al. (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481-487.
Linkermann A, Green DR (2014) Necroptosis. N Engl J Med 370:455-465.
Ma H, Dong Y, Chu Y, Guo Y, Li L (2022) The mechanisms of ferroptosis and its role in alzheimer`s disease. Front Mol Biosci 9:965064.
Ma K, Chen G, Li W, Kepp O, Zhu Y, Chen Q (2020) Mitophagy, Mitochondrial Homeostasis, and Cell Fate. Front Cell Dev Biol 8:467.
Mahoney-Sánchez L, Bouchaoui H, Ayton S, Devos D, Duce JA, Devedjian JC (2021) Ferroptosis and its potential role in the physiopathology of Parkinson`s Disease. Prog Neurobiol 196:101890.
Mandal PK, Shukla D, Tripathi M, Ersland L (2019) Cognitive Improvement with Glutathione Supplement in Alzheimer`s Disease: A Way Forward. J Alzheimers Dis 68:531-535.
Marogianni C, Sokratous M, Dardiotis E, Hadjigeorgiou GM, Bogdanos D, Xiromerisiou G (2020) Neurodegeneration and Inflammation-An Interesting Interplay in Parkinson`s Disease. Int J Mol Sci 21.
Mazhar M, Din AU, Ali H, Yang G, Ren W, Wang L, Fan X, Yang S (2021) Implication of ferroptosis in aging. Cell Death Discov 7:149.
McCann JC, Ames BN (2011) Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging. FASEB J 25:1793-1814.
Njålsson R, Ristoff E, Carlsson K, Winkler A, Larsson A, Norgren S (2005) Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Hum Genet 116:384-389.
Pajares M, A IR, Manda G, Boscá L, Cuadrado A (2020) Inflammation in Parkinson`s Disease: Mechanisms and Therapeutic Implications. Cells 9.
Prata C, Maraldi T, Angeloni C (2022) Strategies to Counteract Oxidative Stress and Inflammation in Chronic-Degenerative Diseases. Int J Mol Sci 23.
Proneth B, Conrad M (2019) Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death Differ 26:14-24.
Ristoff E, Larsson A (2007) Inborn errors in the metabolism of glutathione. Orphanet J Rare Dis 2:16.
Ristoff E, Mayatepek E, Larsson A (2001) Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr 139:79-84.
Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60:1685-1691.
Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M (2008) Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab 8:237-248.
Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660-665.
Shin D, Kim EH, Lee J, Roh JL (2018) Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med 129:454-462.
Stephenson J, Nutma E, van der Valk P, Amor S (2018) Inflammation in CNS neurodegenerative diseases. Immunology 154:204-219.
Stockwell BR et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285.
Tsuji PA, Santesmasses D, Lee BJ, Gladyshev VN, Hatfield DL (2021) Historical Roles of Selenium and Selenoproteins in Health and Development: The Good, the Bad and the Ugly. Int J Mol Sci 23.
Wang S, Yuan YH, Chen NH, Wang HB (2019) The mechanisms of NLRP3 inflammasome/pyroptosis activation and their role in Parkinson`s disease. Int Immunopharmacol 67:458-464.
Wang T, Tomas D, Perera ND, Cuic B, Luikinga S, Viden A, Barton SK, McLean CA, Samson AL, Southon A, Bush AI, Murphy JM, Turner BJ (2022) Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis. Cell Death Differ 29:1187-1198.
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.
Wu S, Zhu C, Tang D, Dou QP, Shen J, Chen X (2021) The role of ferroptosis in lung cancer. Biomark Res 9:82.
Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R, Tang D (2016) Ferroptosis: process and function. Cell Death Differ 23:369-379.
Yan HF, Zou T, Tuo QZ, Xu S, Li H, Belaidi AA, Lei P (2021) Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther 6:49.
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156:317-331.

Yang Y, Luo M, Zhang K, Zhang J, Gao T, Connell DO, Yao F, Mu C, Cai B, Shang Y, Chen W (2020) Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma. Nat Commun 11:433.
Yant LJ, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter JG, Motta L, Richardson A, Prolla TA (2003) The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med 34:496-502.
Yao L, Wu J, Koc S, Lu G (2021) Genetic Imaging of Neuroinflammation in Parkinson`s Disease: Recent Advancements. Front Cell Dev Biol 9:655819.
Yoo SE, Chen L, Na R, Liu Y, Rios C, Van Remmen H, Richardson A, Ran Q (2012) Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radic Biol Med 52:1820-1827.
Yu P, Zhang X, Liu N, Tang L, Peng C, Chen X (2021) Pyroptosis: mechanisms and diseases. Signal Transduct Target Ther 6:128.
Yue M, Wei J, Chen W, Hong D, Chen T, Fang X (2022) Neurotrophic Role of the Next-Generation Probiotic Strain L. lactis MG1363-pMG36e-GLP-1 on Parkinson`s Disease via Inhibiting Ferroptosis. Nutrients 14.
Zhang P, Chen L, Zhao Q, Du X, Bi M, Li Y, Jiao Q, Jiang H (2020) Ferroptosis was more initial in cell death caused by iron overload and its underlying mechanism in Parkinson`s disease. Free Radic Biol Med 152:227-234.
Zhang S, Rocourt C, Cheng WH (2010) Selenoproteins and the aging brain. Mech Ageing Dev 131:253-260.
Zhang ZH, Song GL (2021) Roles of Selenoproteins in Brain Function and the Potential Mechanism of Selenium in Alzheimer`s Disease. Front Neurosci 15:646518.
Zheng J, Conrad M (2020) The Metabolic Underpinnings of Ferroptosis. Cell Metab 32:920-937.
Zheng XJ, Chen WL, Yi J, Li W, Liu JY, Fu WQ, Ren LW, Li S, Ge BB, Yang YH, Zhang YZ, Yang H, Du GH, Wang Y, Wang JH (2022) Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS-regulated ferroptosis. Acta Pharmacol Sin 43:2977-2992.
Zychlinsky A, Prevost MC, Sansonetti PJ (1992) Shigella flexneri induces apoptosis in infected macrophages. Nature 358:167-169.
描述 碩士
國立政治大學
神經科學研究所
109754001
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0109754001
資料類型 thesis
dc.contributor.advisor 陳紹寬zh_TW
dc.contributor.advisor Chen, Shau-Kwaunen_US
dc.contributor.author (Authors) 吳玥彤zh_TW
dc.contributor.author (Authors) Wu, Yue-Tongen_US
dc.creator (作者) 吳玥彤zh_TW
dc.creator (作者) Wu, Yue-Tongen_US
dc.date (日期) 2023en_US
dc.date.accessioned 1-Sep-2023 16:38:37 (UTC+8)-
dc.date.available 1-Sep-2023 16:38:37 (UTC+8)-
dc.date.issued (上傳時間) 1-Sep-2023 16:38:37 (UTC+8)-
dc.identifier (Other Identifiers) G0109754001en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/147337-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 109754001zh_TW
dc.description.abstract (摘要) 鐵依賴性死亡（Ferroptosis）被認為是程序性細胞死亡（PCD）的一種新形式，其特徵包括鐵代謝紊亂、脂質過氧化物積累和氧化應激增加等等，近年來發現其參與多種神經退行性疾病的發病機制，如阿茲海默病、帕金森氏症等，並提及在患者腦中發現了細胞發炎和鐵依賴性死亡的特徵，而穀胱甘肽過氧化物酶4（GPx4）功能的喪失被認為是導致神經系統疾病中細胞發生鐵依賴性死亡的主要因素之一，但對於如何造成上述疾病中神經細胞大量死亡的病理機制仍不清楚。本研究旨在探討 GPx4 基因的敲除是否會引發鐵依賴性死亡及誘發神經炎症，並將進一步探討在其他發炎相關的細胞死亡中的影響。我們使用Gad2Cre/GPx4基因剔除鼠來研究Gpx4基因的剔除在腦中導致的細胞死亡。我們所觀察的所有突變鼠在P7開始可觀察到體重下降等表型，並會在P14前死亡，死亡前表現嚴重的活動下降及痙攣，顯示突變鼠神經系統功能異常。以外，在尼氏染色的結果中突變鼠的大腦前額葉皮層與小腦的細胞組織明顯受到破壞、小腦細胞數量減少及分子層變薄，表明腦部結構異常。通過檢測結構異常的腦區變化，發現突變體小腦中柏金氏細胞及顆粒細胞數量減少、前額葉皮質層及小腦中促發炎因子上調和小膠質細胞形態改變，顯示GABA能神經元死亡的發生可能引發周圍細胞死亡並伴隨發炎反應。實驗發現4-HNe水平的增加並不局限於γ-氨基丁酸能的柏金氏神經元，其在顆粒層也有發現，這表明鐵依賴性細胞死亡訊號可傳遞到其他細胞。最後，我們還研究了發炎可能誘導的其他類型的調節性細胞死亡，包括細胞焦亡和壞死。有趣的是，細胞焦亡途徑在柏金氏神經元和顆粒細胞中得到了促進，而細胞壞死途徑在突變鼠中似乎受到了抑制，我們的研究结果表明GPx4 消融會觸發柏金氏神經元的多種死亡途徑，並向鄰近細胞釋放信號以調節細胞的存活或死亡，組織中複雜的細胞死亡調控網路可能是慢性發展疾病發病機制的關鍵訊息。zh_TW
dc.description.abstract (摘要) Ferroptosis is considered a novel form of programmed cell death (PCD), characterized by disorders of iron metabolism, accumulation of lipid peroxides, and increased oxidative stress, etc. In recent years, that ferroptosis is involved in the pathogenesis of various neurodegenerative diseases, such as Alzheimer`s disease, Parkinson`s disease. Previous studies suggested that features of cellular inflammation and Ferroptosis were found in the brains of patients, suggesting that glutathione peroxidase 4 (GPx4) plays an important role in intracellular antioxidant action. However, loss of GPx4 function is thought to be one of the factors contributing to the onset of ferroptosis in cells with neurodegenerative diseases, but the pathological mechanisms of how ferroptosis is involved in the disease remain unclear. The present study was designed to investigate whether ablation of Gpx4 gene triggers ferroptosis and its effect on neuroinflammation. Also, we will further investigate the roles of Gpx4 in the regulation of cell death, providing potential applications for the treatment of neurodegenerative diseases. Given this, we used Gad2Cre/GPx4 knockout mice to investigate the physiological functions of GPx4 in neuronal cells and whether it causes cell death. All of the mutants we observed had phenotypes such as weight loss starting at P7 and died before P14, showing severe decreased activity and seizure, suggesting that the mutation is a neurological abnormality. Furthermore, the results of Nissl staining revealed significant disruptions in the cellular organization of the prefrontal cortex and cerebellum in the brains of mutants, as well as a decreased cell count and a thinner molecular layer in the cerebellum. These findings indicate abnormal brain structure. Moreover, through the examination of structural abnormalities in the affected brain regions, we found reduced numbers of Purkinje cells and granule cells, upregulation of proinflammatory mediator, and the morphological changes of microglia in the prefrontal cortex and cerebellum of the mutants, indicating that the onset of GABAergic neuronal death may trigger peripheral cell death with a concomitant inflammatory response. The experimental finding that increased levels of 4-HNe were not limited to GABAergic Purkinje neurons, but were also found in the granular layer, suggests that iron apoptosis can be transmitted to other cells. Finally, the researchers also examined other types of regulatory cell death that may be induced by inflammation, including thermal apoptosis and necrosis. Interestingly, the thermoapoptotic pathway was promoted in Purkinje neurons and granule cells, whereas the necroptotic pathway appeared to be inhibited in mutants. Our findings suggest that Gpx4 deficiency triggers multiple death pathways in Purkinje neurons and releases signals to neighboring cells to regulate cell survival or death. The complex network of cell death regulation in tissues may be key information for the pathogenesis of chronic progressive diseases.en_US
dc.description.tableofcontents 第一章 緒論 1
第一節 文獻回顧 1
1.1穀胱甘肽過氧化物酶4（Glutathione peroxidase 4） 1
1.2穀胱甘肽過氧化物酶4在中樞神經系統中的作用 2
1.3 鐵依賴性死亡（Ferroptotsis） 4
1.4 鐵依賴性死亡對神經系統的影響 5
1.5 細胞焦亡（Pyroptosis） 7
第二節 研究目的及策略 9
2.1研究目的及動機 9
2.2實驗設計 9

第二章 材料方法 12
2.1實驗動物 12
2.2蘇木紫-伊紅染色（Hematoxylin-eosin staining, H&E） 12
2.3尼氏染色（Nissl staining） 13
2.4免疫組織染色（Immunohistochemistry, IHC） 13
2.5即時定量聚合酶連鎖反應（Real-time polymerase chain reaction, RT-QPCR） 14
2.6西方墨點（Western blot） 15
2.7統計分析 17

第三章 實驗結果 18
第四章 討論 28
實驗圖表 34
圖一：Gad2Cre/GPx4條件突變鼠出現早期死亡 35
圖二：Gad2Cre/GPx4條件突變鼠表現出神經系統的表型 36
圖三：Gad2Cre/GPx4條件突變鼠各個臟器的組織學分析 39
圖四：Gad2Cre/GPx4條件突變鼠表現細胞分佈及結構異常的神經系統表型 42
圖五：GPx4基因消融使腦結構異常 44
圖六：Gad2Cre/GPx4條件突變鼠的柏金氏神經元和顆粒神經元數量均減少 45
圖七：Gad2Cre/GPx4條件突變鼠小膠質細胞型態變化 48
圖八：Gad2Cre/GPx4條件突變鼠誘發發炎反應 50
圖九：遺傳性消融GPx4可在小鼠大腦發育過程中以细胞自主和非细胞自主的方式觸發鐵依賴性死亡 53
圖十：Gad2Cre/GPx4條件突變鼠小腦的细胞凋亡没有顯增加 55
圖十一：發炎反應不會增強Gad2Cre/GPx4條件突變鼠大腦的细胞壞死 57
圖十二：發炎反應會增強Gad2Cre/GPx4條件突變鼠小腦的细胞壞死 58
圖十三：小腦中神經細胞涉及部分細胞焦亡相關蛋白被抑制的表現 59
圖十四：Gad2Cre/GPx4條件突變鼠腦中缺少GPx4引發改變的假設 60
附錄 61
附錄一：RT混合液體 61
附錄二：cDNA混合液體 61
附錄三：裂解緩衝液（Lysis Buffer） 61
附錄四：Loading dye配方 62
附錄五：Running Gel配方 62
附錄六：Stacking Gel配方 62
附錄七：Tank Buffer配方 63
附錄八：10X Transfer Buffer配方 63
附錄九：實驗使用的引子序列以及溫度 64
參考文獻 65		zh_TW
dc.format.extent 4671039 bytes-
dc.format.mimetype application/pdf-
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0109754001en_US
dc.subject (關鍵詞) 鐵依賴性細胞死亡zh_TW
dc.subject (關鍵詞) 穀胱甘肽過氧化物酶4zh_TW
dc.subject (關鍵詞) 發炎zh_TW
dc.subject (關鍵詞) 細胞凋亡zh_TW
dc.subject (關鍵詞) 細胞壞死zh_TW
dc.subject (關鍵詞) 細胞焦亡zh_TW
dc.subject (關鍵詞) Ferroptosisen_US
dc.subject (關鍵詞) Glutathione peroxidase 4en_US
dc.subject (關鍵詞) inflammationen_US
dc.subject (關鍵詞) Apoptosisen_US
dc.subject (關鍵詞) Necroptosisen_US
dc.subject (關鍵詞) Pyroptosisen_US
dc.title (題名) 腦中缺少GPx4引起細胞死亡之研究zh_TW
dc.title (題名) The study of GPx4-deficiency induced cell death in the brainen_US
dc.type (資料類型) thesisen_US
dc.relation.reference (參考文獻) Alturki NA, McComb S, Ariana A, Rijal D, Korneluk RG, Sun SC, Alnemri E, Sad S (2018) Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis. Cell Death Dis 9:592.
Belaidi AA, Bush AI (2016) Iron neurochemistry in Alzheimer`s disease and Parkinson`s disease: targets for therapeutics. J Neurochem 139 Suppl 1:179-197.
Belaidi AA, Gunn AP, Wong BX, Ayton S, Appukuttan AT, Roberts BR, Duce JA, Bush AI (2018) Marked Age-Related Changes in Brain Iron Homeostasis in Amyloid Protein Precursor Knockout Mice. Neurotherapeutics 15:1055-1062.
Berg D, Youdim MB (2006) Role of iron in neurodegenerative disorders. Top Magn Reson Imaging 17:5-17.
Bjørklund G, Peana M, Maes M, Dadar M, Severin B (2021) The glutathione system in Parkinson`s disease and its progression. Neurosci Biobehav Rev 120:470-478.
Brigelius-Flohé R, Maiorino M (2013) Glutathione peroxidases. Biochim Biophys Acta 1830:3289-3303.
Buijs M, Doan NT, van Rooden S, Versluis MJ, van Lew B, Milles J, van der Grond J, van Buchem MA (2017) In vivo assessment of iron content of the cerebral cortex in healthy aging using 7-Tesla T2*-weighted phase imaging. Neurobiol Aging 53:20-26.
Chan ED, Riches DW (2001) IFN-gamma + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38(mapk) in a mouse macrophage cell line. Am J Physiol Cell Physiol 280:C441-450.
Chen K, Jiang X, Wu M, Cao X, Bao W, Zhu LQ (2021a) Ferroptosis, a Potential Therapeutic Target in Alzheimer`s Disease. Front Cell Dev Biol 9:704298.
Chen L, Hambright WS, Na R, Ran Q (2015) Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis. J Biol Chem 290:28097-28106.
Chen X, Comish PB, Tang D, Kang R (2021b) Characteristics and Biomarkers of Ferroptosis. Front Cell Dev Biol 9:637162.
Chen X, He WT, Hu L, Li J, Fang Y, Wang X, Xu X, Wang Z, Huang K, Han J (2016) Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res 26:1007-1020.
Cheng Y, Song Y, Chen H, Li Q, Gao Y, Lu G, Luo C (2021) Ferroptosis Mediated by Lipid Reactive Oxygen Species: A Possible Causal Link of Neuroinflammation to Neurological Disorders. Oxid Med Cell Longev 2021:5005136.
Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer`s disease transgenic mice. Neuron 30:665-676.
Christgen S, Tweedell RE, Kanneganti TD (2022) Programming inflammatory cell death for therapy. Pharmacol Ther 232:108010.
Conrad M (2009) Transgenic mouse models for the vital selenoenzymes cytosolic thioredoxin reductase, mitochondrial thioredoxin reductase and glutathione peroxidase 4. Biochim Biophys Acta 1790:1575-1585.
D`Souza CA, Heitman J (2001) Dismantling the Cryptococcus coat. Trends Microbiol 9:112-113.
Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F (1993) Glutathione peroxidase, glial cells and Parkinson`s disease. Neuroscience 52:1-6.
Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112-119.
Deponte M (2013) Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Biochim Biophys Acta 1830:3217-3266.
Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, Thomas AG, Gleason CE, Tatonetti NP, Slusher BS, Stockwell BR (2014) Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3:e02523.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, 3rd, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060-1072.
Do Van B, Gouel F, Jonneaux A, Timmerman K, Gelé P, Pétrault M, Bastide M, Laloux C, Moreau C, Bordet R, Devos D, Devedjian JC (2016) Ferroptosis, a newly characterized form of cell death in Parkinson`s disease that is regulated by PKC. Neurobiol Dis 94:169-178.
Duan X, Liu X, Liu N, Huang Y, Jin Z, Zhang S, Ming Z, Chen H (2020) Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation. Cell Death Dis 11:134.
Esworthy RS, Doan K, Doroshow JH, Chu FF (1994) Cloning and sequencing of the cDNA encoding a human testis phospholipid hydroperoxide glutathione peroxidase. Gene 144:317-318.
Febbraro F, Andersen KJ, Sanchez-Guajardo V, Tentillier N, Romero-Ramos M (2013) Chronic intranasal deferoxamine ameliorates motor defects and pathology in the α-synuclein rAAV Parkinson`s model. Exp Neurol 247:45-58.
Federico A, Morgillo F, Tuccillo C, Ciardiello F, Loguercio C (2007) Chronic inflammation and oxidative stress in human carcinogenesis. Int J Cancer 121:2381-2386.
Ferguson LR, Karunasinghe N, Zhu S, Wang AH (2012) Selenium and its` role in the maintenance of genomic stability. Mutat Res 733:100-110.
Fine EJ, Ionita CC, Lohr L (2002) The history of the development of the cerebellar examination. Semin Neurol 22:375-384.
Fine JM, Baillargeon AM, Renner DB, Hoerster NS, Tokarev J, Colton S, Pelleg A, Andrews A, Sparley KA, Krogh KM, Frey WH, Hanson LR (2012) Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice. Exp Brain Res 219:381-390.
Fink SL, Cookson BT (2006) Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol 8:1812-1825.
Friedmann Angeli JP et al. (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16:1180-1191.
Gao P, Cao M, Jiang X, Wang X, Zhang G, Tang X, Yang C, Komuro I, Ge J, Li L, Zou Y (2023) Cannabinoid Receptor 2-Centric Molecular Feedback Loop Drives Necroptosis in Diabetic Heart Injuries. Circulation 147:158-174.
Grossi C, Francese S, Casini A, Rosi MC, Luccarini I, Fiorentini A, Gabbiani C, Messori L, Moneti G, Casamenti F (2009) Clioquinol decreases amyloid-beta burden and reduces working memory impairment in a transgenic mouse model of Alzheimer`s disease. J Alzheimers Dis 17:423-440.
Gu F, Chauhan V, Chauhan A (2015) Glutathione redox imbalance in brain disorders. Curr Opin Clin Nutr Metab Care 18:89-95.
Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, Tardivel A, Heuschling P, Dostert C (2015) NLRP3 Inflammasome Is Expressed and Functional in Mouse Brain Microglia but Not in Astrocytes. PLoS One 10:e0130624.
Haddad JJ, Harb HL (2005) L-gamma-Glutamyl-L-cysteinyl-glycine (glutathione; GSH) and GSH-related enzymes in the regulation of pro- and anti-inflammatory cytokines: a signaling transcriptional scenario for redox(y) immunologic sensor(s)? Mol Immunol 42:987-1014.
Hambright WS, Fonseca RS, Chen L, Na R, Ran Q (2017) Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol 12:8-17.
Haque ME, Akther M, Jakaria M, Kim IS, Azam S, Choi DK (2020) Targeting the microglial NLRP3 inflammasome and its role in Parkinson`s disease. Mov Disord 35:20-33.
Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson`s disease: a target for neuroprotection? Lancet Neurol 8:382-397.
Hu HL, Bennett N, Holton JL, Nolan CC, Lister T, Cavanagh JB, Ray DE (1999) Glutathione depletion increases brain susceptibility to m-dinitrobenzene neurotoxicity. Neurotoxicology 20:83-90.
Ingold I et al. (2018) Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell 172:409-422.e421.
Iskusnykh IY, Zakharova AA, Pathak D (2022) Glutathione in Brain Disorders and Aging. Molecules 27.
Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, Baer R, Gu W (2015) Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520:57-62.
Jiang X, Stockwell BR, Conrad M (2021) Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 22:266-282.
Kayagaki N et al. (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666-671.
Kim J, Byun JW, Choi I, Kim B, Jeong HK, Jou I, Joe E (2013) PINK1 Deficiency Enhances Inflammatory Cytokine Release from Acutely Prepared Brain Slices. Exp Neurobiol 22:38-44.
Kim K (2021) Glutathione in the Nervous System as a Potential Therapeutic Target to Control the Development and Progression of Amyotrophic Lateral Sclerosis. Antioxidants (Basel) 10.
Labrecque CL, Fuglestad B (2021) Electrostatic Drivers of GPx4 Interactions with Membrane, Lipids, and DNA. Biochemistry 60:2761-2772.
Labunskyy VM, Hatfield DL, Gladyshev VN (2014) Selenoproteins: molecular pathways and physiological roles. Physiol Rev 94:739-777.
Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, Sun B, Wang G (2020) Ferroptosis: past, present and future. Cell Death Dis 11:88.
Li J, Li M, Ge Y, Chen J, Ma J, Wang C, Sun M, Wang L, Yao S, Yao C (2022) β-amyloid protein induces mitophagy-dependent ferroptosis through the CD36/PINK/PARKIN pathway leading to blood-brain barrier destruction in Alzheimer`s disease. Cell Biosci 12:69.

Liddelow SA et al. (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481-487.
Linkermann A, Green DR (2014) Necroptosis. N Engl J Med 370:455-465.
Ma H, Dong Y, Chu Y, Guo Y, Li L (2022) The mechanisms of ferroptosis and its role in alzheimer`s disease. Front Mol Biosci 9:965064.
Ma K, Chen G, Li W, Kepp O, Zhu Y, Chen Q (2020) Mitophagy, Mitochondrial Homeostasis, and Cell Fate. Front Cell Dev Biol 8:467.
Mahoney-Sánchez L, Bouchaoui H, Ayton S, Devos D, Duce JA, Devedjian JC (2021) Ferroptosis and its potential role in the physiopathology of Parkinson`s Disease. Prog Neurobiol 196:101890.
Mandal PK, Shukla D, Tripathi M, Ersland L (2019) Cognitive Improvement with Glutathione Supplement in Alzheimer`s Disease: A Way Forward. J Alzheimers Dis 68:531-535.
Marogianni C, Sokratous M, Dardiotis E, Hadjigeorgiou GM, Bogdanos D, Xiromerisiou G (2020) Neurodegeneration and Inflammation-An Interesting Interplay in Parkinson`s Disease. Int J Mol Sci 21.
Mazhar M, Din AU, Ali H, Yang G, Ren W, Wang L, Fan X, Yang S (2021) Implication of ferroptosis in aging. Cell Death Discov 7:149.
McCann JC, Ames BN (2011) Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging. FASEB J 25:1793-1814.
Njålsson R, Ristoff E, Carlsson K, Winkler A, Larsson A, Norgren S (2005) Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Hum Genet 116:384-389.
Pajares M, A IR, Manda G, Boscá L, Cuadrado A (2020) Inflammation in Parkinson`s Disease: Mechanisms and Therapeutic Implications. Cells 9.
Prata C, Maraldi T, Angeloni C (2022) Strategies to Counteract Oxidative Stress and Inflammation in Chronic-Degenerative Diseases. Int J Mol Sci 23.
Proneth B, Conrad M (2019) Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death Differ 26:14-24.
Ristoff E, Larsson A (2007) Inborn errors in the metabolism of glutathione. Orphanet J Rare Dis 2:16.
Ristoff E, Mayatepek E, Larsson A (2001) Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr 139:79-84.
Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60:1685-1691.
Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M (2008) Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab 8:237-248.
Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660-665.
Shin D, Kim EH, Lee J, Roh JL (2018) Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med 129:454-462.
Stephenson J, Nutma E, van der Valk P, Amor S (2018) Inflammation in CNS neurodegenerative diseases. Immunology 154:204-219.
Stockwell BR et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285.
Tsuji PA, Santesmasses D, Lee BJ, Gladyshev VN, Hatfield DL (2021) Historical Roles of Selenium and Selenoproteins in Health and Development: The Good, the Bad and the Ugly. Int J Mol Sci 23.
Wang S, Yuan YH, Chen NH, Wang HB (2019) The mechanisms of NLRP3 inflammasome/pyroptosis activation and their role in Parkinson`s disease. Int Immunopharmacol 67:458-464.
Wang T, Tomas D, Perera ND, Cuic B, Luikinga S, Viden A, Barton SK, McLean CA, Samson AL, Southon A, Bush AI, Murphy JM, Turner BJ (2022) Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis. Cell Death Differ 29:1187-1198.
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.
Wu S, Zhu C, Tang D, Dou QP, Shen J, Chen X (2021) The role of ferroptosis in lung cancer. Biomark Res 9:82.
Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R, Tang D (2016) Ferroptosis: process and function. Cell Death Differ 23:369-379.
Yan HF, Zou T, Tuo QZ, Xu S, Li H, Belaidi AA, Lei P (2021) Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther 6:49.
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156:317-331.

Yang Y, Luo M, Zhang K, Zhang J, Gao T, Connell DO, Yao F, Mu C, Cai B, Shang Y, Chen W (2020) Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma. Nat Commun 11:433.
Yant LJ, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter JG, Motta L, Richardson A, Prolla TA (2003) The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med 34:496-502.
Yao L, Wu J, Koc S, Lu G (2021) Genetic Imaging of Neuroinflammation in Parkinson`s Disease: Recent Advancements. Front Cell Dev Biol 9:655819.
Yoo SE, Chen L, Na R, Liu Y, Rios C, Van Remmen H, Richardson A, Ran Q (2012) Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radic Biol Med 52:1820-1827.
Yu P, Zhang X, Liu N, Tang L, Peng C, Chen X (2021) Pyroptosis: mechanisms and diseases. Signal Transduct Target Ther 6:128.
Yue M, Wei J, Chen W, Hong D, Chen T, Fang X (2022) Neurotrophic Role of the Next-Generation Probiotic Strain L. lactis MG1363-pMG36e-GLP-1 on Parkinson`s Disease via Inhibiting Ferroptosis. Nutrients 14.
Zhang P, Chen L, Zhao Q, Du X, Bi M, Li Y, Jiao Q, Jiang H (2020) Ferroptosis was more initial in cell death caused by iron overload and its underlying mechanism in Parkinson`s disease. Free Radic Biol Med 152:227-234.
Zhang S, Rocourt C, Cheng WH (2010) Selenoproteins and the aging brain. Mech Ageing Dev 131:253-260.
Zhang ZH, Song GL (2021) Roles of Selenoproteins in Brain Function and the Potential Mechanism of Selenium in Alzheimer`s Disease. Front Neurosci 15:646518.
Zheng J, Conrad M (2020) The Metabolic Underpinnings of Ferroptosis. Cell Metab 32:920-937.
Zheng XJ, Chen WL, Yi J, Li W, Liu JY, Fu WQ, Ren LW, Li S, Ge BB, Yang YH, Zhang YZ, Yang H, Du GH, Wang Y, Wang JH (2022) Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS-regulated ferroptosis. Acta Pharmacol Sin 43:2977-2992.
Zychlinsky A, Prevost MC, Sansonetti PJ (1992) Shigella flexneri induces apoptosis in infected macrophages. Nature 358:167-169.		zh_TW