亨丁頓氏症是一種顯性遺傳疾病，致病原因為突變的亨丁頓基因產生過多的CAG三核苷酸重複序列，進而造成亨丁頓蛋白質N端帶有異常的多穀氨酸長鏈。亨丁頓基因廣泛的表現在人體的各個組織，因此突變亨丁頓蛋白質會聚集在中樞神經系統和周邊組織，例如心臟和肝臟，造成全身性的病狀。為了避免這些病狀的產生，用來清除突變亨丁頓蛋白質的泛素-蛋白酶體系統和細胞自噬是有潛力的治療對策之一。本篇研究的目的為在亨丁頓氏症發病前的細胞和動物模式中比較這兩種清除路徑在中樞神經系統和周邊組織的表現。本篇論文在兩種神經細胞株，以及四種周邊組織細胞株中表現突變亨丁頓蛋白質做為細胞實驗的材料。動物模式則是採用亨丁頓氏症基因轉殖小鼠，為帶有突變亨丁頓蛋白質第一外顯子和增強綠螢光蛋白的融合蛋白的小鼠模式。根據之前的研究發現，這些亨丁頓小鼠在8.5個月時顯現動作功能缺失的情形，為了探討亨丁頓氏症發病前泛素-蛋白酶體系統和細胞自噬的表現，我們選擇三個不同的時間點(2、5和8個月)的亨丁頓氏症基因轉殖小鼠，利用西方墨點法來比較泛素-蛋白酶體系統標誌”泛素”和細胞自噬標誌”LC3-II”的表現。細胞實驗結果顯示，表現突變亨丁頓蛋白質的神經細胞其LC3-II的表現顯著性的上升，但在腎臟細胞則隨著時間顯著性的下降。然而泛素聚集在表現突變亨丁頓蛋白質的神經細胞及腎臟細胞隨著時間都有顯著性的增加。在動物實驗方面，亨丁頓小鼠的大腦皮質組織、紋狀體組織、肺臟組織及肝臟組織在8個月時泛素有明顯聚集的情況，而LC3-II的表現在8個月大的亨丁頓小鼠心臟組織有顯著性的下降。實驗結果顯示泛素-蛋白酶體系統在大腦皮質組織、紋狀體組織、肺臟組織及肝臟組織在發病前已經損壞。然而只有心臟組織其細胞自噬的活性有下降。這些發現顯示，在我們亨丁頓氏症發病前的小鼠模式中，泛素-蛋白酶體系統在大腦皮質組織、紋狀體組織、肺臟組織和肝臟組織比細胞自噬來的更為重要。

Huntington disease (HD) is an autosomal dominant disorder caused by a mutantion of CAG repeat expansion in huntingtin (HTT) gene, resulting an abnormally long polyglutamine tract at the N terminus of HTT. The HTT gene is widely expressed in human tissues, and mutant HTT protein forms aggregates in central nervous system (CNS) and several peripheral tissues, such as heart and liver, leading to widespread pathology. In order to prevent pathological phenotypes, clearance of mutant HTT, mediated by both the ubiquitin–proteasome system (UPS) and autophagy, is one of potential strategies. Therefore, the aim of this study was to compare these two degradation pathways in CNS and peripheral tissues before the onset of HD in vitro and in vivo. Two neuronal and four peripheral tissue cell lines expressing mutant huntingtin were used in cell experiments. HD transgenic mice carrying GFP fused with mutant HTT exon 1 were used in this study. According to our previous studies, these HD transgenic mice showed the onset of motor deficit after 8.5 months of age. In order to determine UPS and autophagy before the onset of HD, we chose three different age points (2, 5 and 8 months) in HD transgenic mice to compare expression profiles of ubiquitin, an UPS marker, and LC3-II, an autophagy marker, by western blot analyses. The data showed that the expression of LC3-II significantly increased in neuronal cells but significantly decreased in kidney cells after expressing mutant huntingtin. However, the expression of ubiquitin positive aggregate both in neuronal cells and kidney cells significantly increased after expressing mutant huntingtin in a time dependent manner. Next, in vivo data showed that the expression of ubiquitin positive aggregate in cortex, striatum, lung and liver significantly increased in 8 months old HD mice compared to those of 8 months old control mice. In addition, the expression of LC3-II in heart, but not other tissues, significantly decreased in 8 months old HD mice compared to those of control mice. These results indicated that UPS was impaired in cortex, striatum, lung and liver before the onset in our HD mouse model. However, the activity of autophagy was only reduced in heart. In conclusion, our findings showed that UPS was more important than autophagy in cortex, striatum lung and liver, but not in heart, before the onset of HD.

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