二氫神經醯胺去飽和酶在神經退化之分子機制研究

Abstract

神經鞘脂 (Sphingolipids)在神經系統中含量豐富，對大腦的發育和功能至關重要。它們的特性會根據其結構變異而發生顯著的變化，包括極性官能基(polar head groups)、脂肪酸鏈 (Fatty acyl chain)和神經鞘氨醇基 (sphingoid base)。二氫神經醯胺去飽和酶 (Dihydroceramide desaturase)將 C4-5 雙鍵加到神經鞘氨醇基上，調節二氫神經鞘脂和神經鞘脂的濃度，而這兩者之間的平衡是決定膜特性的關鍵因素。值得注意的是，二氫神經鞘脂的增加與神經退化性疾病有關，而編碼二氫神經醯胺去飽和酶的 DEGS1 基因的功能喪失變異與神經系統疾病有關。我們之前建立了infertile crescent（ifc）-剔除的果蠅模型，它是與DEGS1功能保守的同源基因。ifc的缺失誘發了眼睛的光依賴性神經退化，引起過多的氧化壓力和細胞自噬活性。我的博士研究進一步闡述了喪失ifc所引起的這兩個細胞機制。結果顯示ifc會透過 Rac1 訊號調節神經元氧化壓力和自噬功能。具體而言，ifc調節活性 Rac1在細胞中的位置，而其缺失會導致 Rac1 錯位和 NADPH 氧化酶的活化，造成氧化壓力。此外，ifc的基因過表達會增強 Rac1-Atg8 的結合，抑制自溶體的成熟，在眼球退化過程中提供對自噬細胞死亡的保護。這些發現為二氫神經醯胺去飽和酶在神經保護中的角色提供了重要的啟示，並為與神經鞘脂失調相關的神經退化性疾病提出了潛在的治療目標。最後，本論文研究的成果呈現在兩篇研究文章發表於國際期刊。

Sphingolipids are abundant in the nervous system and crucial for brain development and function. Their properties change significantly based on their structure variability, including the polar headgroup, the acyl chain, and the sphingoid base. Dihydroceramide desaturase adds the C4-5 double bond to the sphingoid base, modulating the balance between dihydrosphingolipids and sphingolipids, which are crucial determinants of membrane properties. Notably, increases in dihydrosphingolipids have been associated with neurodegenerative diseases, and loss-of-function variants in the DEGS1 gene encoding dihydroceramide desaturase have been linked to neurological disorders. We previously established the fly model of infertile crescent (ifc)-knockout, which is the functional ortholog of DEGS1. Loss of ifc induced light-dependent neurodegeneration in the eye, showing increased oxidative stress and autophagy activities. My doctoral research further elucidated the mechanisms underlying these two cellular hallmarks of ifc-knockout eyes. The results indicated that ifc modulates neuronal oxidative stress and autolysosome function through Rac1-signaling. Specifically, ifc regulates subcellular localization of active Rac1, while its absence led to Rac1 mislocalization and the activation of NADPH oxidase, causing oxidative stress. In addition, the overexpression of ifc enhances Rac1-Atg8 association, which inhibits the maturation of autolysosome, offering protection against autophagic cell death during eye degeneration. These findings provide critical insights into the role of dihydroceramide desaturase in neuroprotection and suggest potential therapeutic targets for neurodegenerative diseases associated with sphingolipid dysregulation. Finally, the results of this thesis research are presented in two research articles published in international journals.