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研究生:張毓秦
研究生(外文):Yu-Chin Chang
論文名稱:細胞脂噬作用對神經磷脂質失衡導致退化的保護機制
論文名稱(外文):Activation of lipophagy protects neurons from neurodegeneration caused by sphingolipid imbalance
指導教授:詹智強詹智強引用關係
口試委員:陳光超周雅惠李秀香
口試日期:2016-06-21
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:70
中文關鍵詞:細胞脂噬作用神經磷脂質神經退化
外文關鍵詞:lipophagysphingolipidneurodegeneration
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神經磷脂質 (Sphingolipid) 為神經細胞膜之重要分子,因此其胞內組成須被嚴謹調控。在果蠅神經磷脂質新合成路徑中,基因infertile crescent (ifc) 為演化上具高度保守性的脂質修飾酵素Dihydroceramide (DHC) desaturase,負責將dihydroceramide (DHC) 轉變為神經醯胺 (ceramide)。具生物活性的神經醯胺 (ceramide) 的失衡與許多神經退化疾病相關,然而關於其上游的dihydroceramid (DHC) 對於神經功能的影響仍未知。為探討ifc於神經所扮演的角色,我們製造出ifc-KO基因剔除果蠅。Sphingolipidomic analysis顯示失去ifc導致DHC增加。ifc-KO果蠅眼睛在連續光刺激下會導致感光細胞退化。透過ifc-KO感光細胞突變群組分析 (clonal analysis),我們在連續光刺激下,觀察到脂噬 (lipophagy) 結構堆積以及活性氧物種 (ROS) 染劑H2DCF的訊號上升,因此推論DHC堆積會活化脂噬作用並誘導ROS 增加。然而,神經退化是否歸因於脂噬作用而造成細胞死亡或是活性氧物種 (ROS) 所致,則仍有待實驗證明。當減少ifc表現時,酸性胞器中的Atg8/LC3 puncta會增加,而且溶酶體的蛋白酶Cathepsins會提升,這表示活化的脂噬作用可以促進溶酶體的活性。ifc依賴性神經退化可藉由餵食抗氧化劑AD4部分拯救,表示活性氧物種 (ROS) 是造成神經退化的部分原因。此外,在ifc-KO中,活性氧物種的提升及油滴的堆積均能藉由餵食誘導細胞自噬作用發生的Rapamycin所部分抑制,因此推論在ifc依賴性神經退化細胞中提升脂噬作用,具有部分保護功能。反之,脂噬作用可藉由餵食AD4而下調,表示活性氧物種 (ROS) 為導致保護性的脂噬作用的成因。綜合上述,失去ifc會導致DHC堆積與活性氧物種 (ROS) 產生,後者隨後激活脂噬作用以保護神經免於退化。這些實驗結果支持我們的假說:DHC具有生物活性;其堆積會造成神經退化,且在這過程中細胞會活化脂噬作用以作為因應的保護機制。

Sphingolipids are essential membrane components of the neuron; hence their levels need to be tightly regulated. Infertile crescent (Ifc) is an evolutionarily conserved dihydroceramide (DHC) desaturase which converts DHC to Ceramide (Cer) for the de novo synthesis of Cer in Drosophila. While the imbalance of Cer, a bioactive sphingolipid, has been associated with several neurodegenerative diseases, the neuronal function of its precursor DHC remains unknown. To investigate the role of ifc, we generated ifc knockout flies (ifc-KO). Sphingolipidomic analysis showed that loss of ifc resulted in increased DHC. Prolonged light stimuli to the ifc-KO eye led to activity-dependent degeneration of photoreceptors. Clonal analysis of ifc-KO photoreceptors revealed the accumulation of lipophagic structure and the increased H2DCF signals upon light stimuli, suggesting that DHC accumulation may activate lipophagy and induce the production of reactive oxygen species (ROS). However, it remains to be determined whether the degeneration is attributed to lipophagic cell death or the ROS insults. Reduction of ifc led to the increase of Atg8/LC3 puncta in the acidified compartment and elevation of lysosomal proteases, indicating the activated lipophagy can promote subsequent lysosomal function. ifc-dependent neurodegeneration can be partially rescued by an antioxidant AD4, indicating that ROS is at least partially responsible for the degeneration. In addition, both ROS elevation and lipid accumulation in ifc-KO was suppressed by treating with the autophagy inducer Rapamycin, suggesting that enhanced lipophagy plays a protective role in ifc-dependent neurodegeneration. Conversely, lipophagy can be downregulated by AD4, indicating ROS insults lead to the feedback upregulation of protective lipophagy. In summary, loss of ifc results in DHC accumulation and ROS generation, the latter of which subsequently activates lipophagy to protect against neurodegeneration. These findings support our hypothesis that DHC is bio-active and lipophagy can be protective, highlighting their potential as therapeutic targets for regulating sphingolipid homeostasis.

目錄
口試委員會審定書...i
誌謝.............ii
摘要............iii
Abstract........iv
第一章 實驗背景....4
1.1 神經磷脂質新合成路徑 (Sphingolipid de novo synthesis pathway) 平衡對於神經退化之影響.......5
1.2 Dihydroceramide desaturase於哺乳類細胞及果蠅中之功能..8
1.3 Dihydroceramide於細胞自噬作用中扮演之角色.............9
1.4 神經磷脂質與細胞自噬作用............................10
1.5 活性氧物種 (ROS)、細胞自噬作用與神經退化之關係........11
第二章 實驗材料與方法......13
2.1 果蠅株及培養方法.....14
2.2 果蠅食物培養基製備...16
2.3 視神經電位紀錄 (Electroretinogram)....16
2.4 免疫螢光染色 (Immunohistochemistry)...17
2.5 免疫染色抗體清單 (IHC Antibody List)..18
2.6 西方墨點法 (Western blotting).........19
2.7 ifc基因剃除 (gene knockout) 果蠅製作..20
2.8 群組分析 (Clonal analysis)...........21
2.9 即時聚合酶鏈式反應 (Real-Time Quantitative PCR)..21
2.10 果蠅餵食藥劑實驗製備....22
2.11 神經母細胞瘤細胞株 (SH-SY5Y) 培養及染色....23
第三章 實驗結果.....24
3.1 神經細胞中的ifc對於生物個體的存活是必需的、且具有演化上的保守性......25
3.2 失去ifc會導致果蠅成蟲視神經細胞活性依賴退化.....26
3.3 失去ifc造成細胞內DHC堆積及Cer減少......26
3.4 失去ifc導致DHC的堆積是視神經退化的主因,並非為缺乏下游產物Cer所致....27
3.5 Ifc蛋白在神經細胞中位於次級核內體 (late endosome)...27
3.6 失去ifc會導致視神經活性氧物種 (ROS) 增加....28
3.7 ifc-KO視神經中有脂噬作用 (lipophagy) 的活化....28
3.8 ifc-KO所提升的細胞自噬作用為一保護機制,使細胞免於活性氧物種的攻擊....30
3.9 DHC具有生物活性,DHC堆積會導致神經毒性....31
第四章 實驗討論....32
4.1 ifc於神經細胞及神經膠細胞 (glia cell) 扮演重要角色..33
4.2 Ifc於神經細胞之新定位....33
4.3 細胞自噬作用與神經磷脂質之恆定....34
4.4 在神經退化疾病中,DHC為一具有生物活性的神經磷脂質....34
第五章 未來實驗方向....36
5.1 DHC在神經退化相關疾病扮演的角色....37
5.2 排除ifc-KO為non-activity dependent degeneration...37
5.3 Ifc與Rab7之關聯性...38
第六章 實驗圖表....39
第七章 參考文獻....64

圖目錄
Figure. 1 神經磷脂質新合成路徑 (Sphingolipid de novo synthesis pathway)....6
Figure. 2 Ifc與其人類同源蛋白 (homolog) 之胺基酸序列比對..9
Figure. 3 製作ifc無效等位基因 (null allele) 之果蠅...40
Figure. 4 ifc基因剔除果蠅呈現發育遲緩且於二齡幼蟲時死亡..42
Figure. 5 失去ifc會導致果蠅成蟲視神經細胞的活性依賴退化..44
Figure. 6 失去ifc會造成細胞內DHC堆積以及Cer減少........46
Figure. 7 DHC的堆積是ifc-KO視神經退化的主因...........48
Figure. 8 Ifc蛋白位於神經細胞的次級核內體(late endosome)......50
Figure. 9 失去ifc會導致細胞內活性氧物種增加.....52
Figure. 10 ifc-KO視神經中有脂噬作用 (Lipophagy) 之活化..54
Figure. 11 失去ifc會提升細胞自噬作用.....56
Figure. 12 ifc-KO所提升之細胞自噬作用為保護神經細胞免於活性氧物種之傷害....58
Figure. 13 提升細胞自噬作用能使ifc-KO中堆積之油滴減少...60
Figure. 14 DHC具有生物活性...62

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