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| Title: | 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 |
| Authors: | 吳玥彤
Wu, Yue-Tong |
| Contributors: | 陳紹寬
Chen, Shau-Kwaun
吳玥彤
Wu, Yue-Tong |
| Keywords: | 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 |
| Date: | 2023 |
| Issue Date: | 2023-09-01 16:38:37 (UTC+8) |
| Abstract: | 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. |
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| Description: | 碩士
國立政治大學
神經科學研究所
109754001 |
| Source URI: | http://thesis.lib.nccu.edu.tw/record/#G0109754001 |
| Data Type: | thesis |
| Appears in Collections: | [神經科學研究所] 學位論文
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