亨廷頓舞蹈症(Huntington’s disease)是因為huntingtin(Htt)基因exon1中的CAG不正常增長,所造成的一種顯性神經退化性疾病,其主要病徵為突變的亨廷頓蛋白(huntingtin)會不正常的聚集堆積在神經元中。亨廷頓蛋白能夠與多種蛋白質有交互作用已調控細胞中的作用機制。已知亨廷頓相關蛋白40會和亨廷頓蛋白結合，調控早期內噬體在微管上的運輸。在Hdh140Q/140Q亨廷頓舞蹈症模式小鼠中發現亨廷頓相關蛋白40蛋白表現量會顯著下降，在實驗室先前研究中發現，STHdhQ111/Q111和大鼠轉殖ST14A-120Q細胞中，亨廷頓相關蛋白40表現量都會有顯著的降低，目前對於亨廷頓相關蛋白40詳細作用機制仍不清楚。亨廷頓舞蹈症會對不同胞器造成損害，並使其功能失調，導致各種細胞壓力的生成。目前細胞壓力分為內質網壓力、高基氏體壓力以及氧化壓力三種。一旦內質網裝載過多的未摺疊蛋白質以及錯誤摺疊的蛋白質，便會產生內質網壓力，細胞會去活化未摺疊蛋白質反應(unfolded protein response, UPR) 以應付蛋白質折疊的改變。當高基氏體受到損害，會使高基氏體蛋白質ACBD3表現量顯著增加並且廣泛分布細胞質中，引起高基氏體壓力。粒線體中ROS的含量平衡受到破壞，便會產生氧化壓力(oxidative stress)，破壞粒線體的動態平衡，加速細胞老化速度，甚至直接導致細胞死亡。當粒線體受到嚴重的氧化傷害，會藉由動態平衡機制，經由連續的分裂(fission)和融合(fusion)相互作用，用以維持粒線體細胞型態，回復或是移除受損的胞器。在本篇論文我們探討內生性亨廷頓相關蛋白40在HD造成不同細胞壓力過程中扮演的角色。首先在Neuro2a細胞中處理能夠誘導不同細胞壓力的藥物。實驗結果發現在藥物誘導內質網壓力和高基氏體壓力情況下，會使亨廷頓相關蛋白40表現量顯著下降，氧化壓力對亨廷頓相關蛋白40表現量則沒有顯著影響。接著利用knockdown shRNAs來降低內生性亨廷頓相關蛋白40在細胞中的表現量進行研究。結果發現亨廷頓相關蛋白40不會誘導內質網壓力生成。另外降低內生性亨廷頓相關蛋白40表現量，會影響高基氏體型態，增加高基氏體擴散的比例。PHB是一由PHB1和PHB2組成的二聚體，鑲嵌在粒線體膜上的蛋白質，具有調控粒線體DNA表現的功能。研究指出在MEFs、HeLa和肌肉細胞中，降低PHB表現量，會造成粒線體分裂。另外文獻說明，STHdhQ111/Q111相較於STHdhQ7/Q7細胞，會增加粒線體分裂，使粒線體融合功能受損。而實驗室先前研究發現大鼠轉殖ST14A-120Q細胞中，亨廷頓相關蛋白40和PHB1表現量會有顯著的下降。因此我們推論降低內生性亨廷頓相關蛋白40可能會對粒線體動態平衡產生影響，結果發現降低內生性亨廷頓相關蛋白40表現量會使粒線體分裂比列顯著增加，並且影響粒線體分裂與融合機制相關蛋白表現量。進一步研究發現，降低內生性亨廷頓相關蛋白40表現量會影響電子傳遞鏈相關蛋白表現量，導致細胞中ATP濃度變化。在降低內生性亨廷頓相關蛋白40表現量並且同時過度表現PHB1或是HttQ23F則能夠改善粒線體分裂的情況。進一步研究內生性亨廷頓相關蛋白40在細胞中的生理功能，發現降低內生性亨廷頓相關蛋白40影響細胞訊號傳遞，能夠抑制Akt路徑，活化JNK路徑。另外，過度表現亨廷頓相關蛋白40會增加MG132生成的聚集體，亨廷頓相關蛋白40可能影響聚集體降解錯誤折疊蛋白質作用機制。最後我們想進行蛋白質結晶實驗，藉以獲得亨廷頓相關蛋白40蛋白結晶結構，而在進行GST-hHAP40純化實驗過程中，發現hHAP40會和粒線體蛋白質OmpF產生交互作用。

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of polyglutamine repeats in the gene for huntingtin (Htt). In HD the corpus striatum selectively degenerates despite uniform expression of mutant huntingtin (mHtt) throughout the brain and body. Previous study showed that Htt-HAP40 complex is an effector of Rab5 that regulates dynamics of early endosomes. Striatal synaptosomes of 12 month old Hdh140Q/140Q mice had lower levels of HAP40. In HD studies indicated, damaged ER, golgi and mitochondria are dysfunctional, result in cellular stresses. Alterations in mitochondria and increased oxidative stress are associated with the disease progression in Huntington’s disease (HD). Endoplasmic reticulum (ER) stress and oxidative damage are linked through the close communication between the ER and mitochondria. It is unclear that the HAP40 mechanism. Here, We assess the role of HAP40 in cellular stresses. Our data revealed that HAP40 is downregulated by ER stress and golgi stress. We found that depletion of HAP40 affected golgi morphology. However, neither depletion nor overexpresion of HAP40 induces ER stress. Our previous studies showed that ST14AHtt-Q120 low, 1-548, HUMAN cell had lower levels of HAP40 and PHB1. PHB1 can be a mitochondria marker. Therefore, we tested wether depletion of HAP40 affect mitochondria dynamics. Results indicated that deplation of HAP40 increases mitochondria fragmention. Western blot assays showed that depletion of HAP40 affected mtiochondria fission and fusion related protein levels. Depletion of HAP40 also affected signaling pathways, inhibiting Akt pathway and activing JNK pathway. Finally, we found that overexpresion of PHB1 or HttQ23F could rescue mitochondria fragmention by depletion of HAP40; In the process of purifying GST-HAP40 for structural analysis, we found that HAP40 could interact with OmpF.

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