亨廷頓氏症是因亨廷頓蛋白的多聚麩醯胺過度擴張導致的漸進性神經退化性疾病。亨廷頓蛋白與多種蛋白交互作用並參與細胞調控，其中包括功能尚未釐清的亨廷頓相關蛋白40。已知在亨廷頓氏症模式小鼠的紋狀體細胞以及患者腦部中發現亨廷頓相關蛋白40大量表現，然而，亨廷頓相關蛋白40過度表達和亨廷頓氏症病徵之間的關係仍不明確。結果顯示亨廷頓相關蛋白40過度表達會增加突變型亨廷頓蛋白聚集體的數量並且降低泛素蛋白酶體接受器-泛素結合受體13的蛋白表現量。進一步的研究結果發現，在亨廷頓相關蛋白40過度表達下增加泛素結合受體13可減少突變型亨廷頓蛋白聚集體數量。 另一方面，也發現在泛素結合受體13缺失時會增加突變型亨廷頓蛋白聚集體。綜合上述，我們認為泛素結合受體13對於去除突變型亨廷頓蛋白聚集體扮演一重要角色，此外，泛素結合受體13介導亨廷頓相關蛋白40所誘導的突變型亨廷頓蛋白聚集體增加。亨廷頓氏症的紋狀體神經細胞死亡與粒線體動態失衡和功能異常相關。然而，粒線體功能缺失的機制仍然是未知的。我們的結果顯示亨廷頓相關蛋白40過度表達使泛素結合受體13表現量下降進而導致粒線體功能缺失並降低紋狀體神經細胞存活率。結果進一步發現泛素結合受體13缺失造成的粒線體型態改變及功能異常，其機制是透過增加Drp1蛋白在Ser616位置上的磷酸化。在給予泛素結合受體13後可降低Drp1Ser616的磷酸化蛋白表現量，並改善亨廷頓相關蛋白40過度表達所誘導的ROS增加、促進粒線體分裂及功能缺失、紋狀體細胞死亡等細胞的缺陷。因此，綜合上述結果發現泛素結合受體13介導亨廷頓相關蛋白40所誘導的粒線體動態失衡和功能異常。橄欖苦苷是從橄欖樹葉中分離的酚類化合物，先前研究已指出橄欖苦苷可增強蛋白酶體的活性，故測試是否能藉由橄欖苦苷來調節亨廷頓相關蛋白40誘導的細胞功能缺陷。 實驗結果發現橄欖苦苷給予可增加亨廷頓相關蛋白40過度表達細胞和表現突變型亨廷頓蛋白紋狀體細胞的細胞存活率。此外，在橄欖苦苷給予後，顯著降低細胞中突變型亨廷頓蛋白聚集體堆積。相關文獻發現在亨廷頓氏症中ROS增加及抗氧化防禦系統降低與紋狀體神經細胞死亡有極大關聯性。研究結果發現在亨廷頓相關蛋白40過度表達細胞和表現突變型亨廷頓蛋白的紋狀體細胞中給予橄欖苦苷可顯著降低粒線體分裂和ROS含量，增加細胞ATP含量。 綜合實驗結果發現，橄欖苦苷具調節粒線體功能以及減少突變型亨廷頓蛋白聚集體堆積，提供神經退化性疾病一個新的治療方向與目標。

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by an N-terminal expansion of polyglutamine stretch (polyQ) of huntingtin (Htt) protein. HAP40 is a huntingtin-associated protein with unknown cellular functions. Increased HAP40 expression has been reported in the brain of HD patients and HD mouse model. However, the relationship between the elevation of HAP40 and HD etiology remains elusive. In this study, we demonstrated that overexpression of HAP40 enhanced accumulation of mutant Htt aggregates and caused defects in proteasome function. Specifically, excess HAP40 interfered with adhesion regulating molecule 1 (ADRM1), a proteasome ubiquitin receptor, to regulate the proteasome-dependent pathway. Increasing ADRM1 in the presence of excess HAP40 alleviated mutant Htt aggregates. Reducing ADRM1 in the absence of excess HAP40, on the other hand, increased mutant Htt aggregates. Our data provide evidence to support that ADRM1 plays an important role in mediating removal of mutant Htt aggregates when excess HAP40 is present.
Striatal neuron death in HD is associated with abnormal mitochondrial dynamics and functions. However, the mechanisms for this mitochondrial dysregulation remain elusive. Here we show that HAP40 overexpression causes mitochondrial dysfunction and reduces cell viability in the striatal neurons. HAP40-associated mitochondrial dysfunction is associated with reduction of adhesion regulating molecule 1 (ADRM1) protein. Depletion of ADRM1 by shRNAs impaired mitochondrial functions and increased mitochondrial fragmentation in striatal cells. Moreover, reducing ADRM1 levels enhanced activity of fission factor dynamin-related GTPase protein 1 (Drp1) via an increased phosphorylation at serine 616 of Drp1 (Drp1Ser616). Restoring ADRM1 protein levels was able to reduce HAP40-induced ROS levels and mitochondrial fragmentation and improved mitochondrial functions and cell viability. Our studies suggest that HAP40-mediated reduction of ADRM1 alters the mitochondrial fission activity and results in mitochondrial fragmentation and mitochondrial dysfunction. Besides, we show that oleuropein, a phenolic compound isolated from the olive tree leaves, increases cell viability of the HAP40 expressing cells and mutant STHdhQ111/Q111 striatal cells. We also found that the accumulation of mutant huntingtin was reduced after oleuropein treatment. Increased oxidative stress and decreased antioxidant defense system are associated with striatal neuron death in HD. We found that oleuropein attenuated mitochondrial fragmentation and ROS levels and increased cellular ATP content. Our study provides evidence that identify oleuropein as a potential treatment for neuronal dysfunctions in HD.

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