亨廷頓舞蹈症是一種顯性遺傳的神經退化性疾病，其主要致病原因為 HTT 基因上的第一外顯子有不正常的 CAG 序列擴增，使 Htt 蛋白在氨基端產生poly Q 的片段擴增進而形成突變型 Htt 蛋白。該基因在突變之後影響的區域主要是腦部，包括紋狀體、大腦皮層等區域。已知突變型 Htt 蛋白對於細胞的影響包括蛋白酶體失活、粒線體損傷、蛋白團聚體堆積、氧化壓力上升、細胞自噬障礙等等，導致神經變性，最終使細胞死亡，目前仍沒有有效的治療方法。突變型細胞 STHdhQ111/Q111 中 Htt 的蛋白表現量比野生型細胞 STHdhQ7/Q7 來的低，且STHdhQ111/Q111 細胞也出現了明顯的粒線體損傷以及氧化壓力增加。由於粒線體的蛋白質約 99% 都來自於細胞核內基因，粒線體功能的維持仰賴於正常的粒線體蛋白輸入以及適當的粒線體質量控制，已經有研究發現蛋白酶體會透過影響粒線體質量控制來調控粒線體的功能以及完整性，而先前有研究指出在 HD 的模式細胞及模式小鼠中過度表達 PSME3/PA28γ 會增加細胞存活率以及蛋白酶體活性，且也有研究觀察到在人類成纖維細胞中過度表達 PSMB5/β5 可以增加蛋白酶體活性也能增加細胞在氧化壓力刺激的環境下的存活率。除了 PSME3/PA28γ 和 PSMB5/β5，已經有研究指出UCHL1功能降低可能會導致神經變性，實驗室已經發現在 STHdhQ111/Q111 細胞內 UCHL1 的表現量明顯低於 STHdhQ7/Q7，而近期的研究發現 UCHL1 透過影響 Mitofusin-2參與粒線體的質量控制。當在 STHdhQ111/Q111 細胞分別過度表達了 PSME3/PA28γ 和 PSMB5/β5，粒線體的膜電位都有回升，且粒線體中的超氧陰離子也有顯著的減少，然而只有過度表達 PSME3/PA28γ 才會減少細胞內的 ROS，過度表達 PSMB5/β5 會使細胞內氧化壓力上升。在 STHdhQ111/Q111 細胞中過度表達 UCHL1 主要影響的部分為氧化壓力，會降低粒線體內超氧陰離子以及細胞內的 ROS，但不影響粒線體膜電位。此外，已經有研究發現部分 Htt 蛋白分布於粒線體，且突變型 Htt蛋白會損傷粒線體的功能，我們在 Htt 蛋白表現量較低的 STHdhQ111/Q111 細胞中分別過度表達了野生型以及突變型的全長 Htt 蛋白，只有在過度表達野生型全長的 Htt 蛋白才會明顯減少粒線體內超氧陰離子。過度表達 PSME3/PA28γ、UCHL1、PSMB5/β5和野生型全長 Htt 蛋白能夠增強粒線體功能，且四種蛋白對於 HD 模式中的粒線體損傷影響皆不相同，而影響的機制需要再多加研究。

Huntington's disease (HD) is an inherited and dominant neurodegenerative disease. The main cause of the disease is the abnormal CAG sequence amplification in exon 1 of Htt gene, which leads to the extension of polyglutamine stretch (poly-Q) in Htt protein. Defective mitochondrial function and proteasome activities have been deserved in HD patients’ brains. Recent research showed that overexpression of PA28γ (an UPS activating protein) enhanced proteasome activity in HD neuronal model cells and HD YAC128 mice. Other research revealed that overexpression of PSMB5/β5 not only increased proteasomes activity but also increase the survival rate in oxidative stress in human fibroblasts. In addition to PSME3/PA28γ and PSMB5/β5, studies had pointed out that the reduced function of UCHL1 may lead to neurodegeneration. We found that overexpression of PA28γ not only improves mitochondrial function but also reduces oxidative stress. Overexpression of PSMB5 and UCHL1 improves mitochondrial function as well. Though the molecular function of Htt remains elusive, recent research revealed that Htt localized in mitochondria. Overexpression of full-length Htt did not affect mitochondrial membrane potential, but overexpressed wild type Htt (Htt 23QF-Myc) reduced mitochondrial ROS level. Further experiments are required to decipher the mechanism of Htt protein and UPS system in the mitochondrial defect and their role in the etiology of HD.

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