亨廷頓舞蹈症是一種顯性遺傳的神經退化性疾病，致病原因為亨廷頓蛋白發生突變，造成CAG三核苷酸重複序列異常擴增，促使錯誤摺疊的亨廷頓蛋白形成聚集體並堆積於神經細胞中。亨廷頓蛋白的功能尚未完全釐清，但其會與許多蛋白交互作用來參與細胞機制的調控，其中亨廷頓相關蛋白40會和亨廷頓蛋白的羧基端結合，調控早期內噬體在微管上的運輸。實驗室先前發現亨廷頓相關蛋白40過度表現時會增加K48泛素化蛋白的堆積及促進細胞自噬流量，已知K48所形成的多泛素鏈蛋白會被送往蛋白酶體進行降解，且細胞可藉由促進細胞自噬來彌補泛素-蛋白酶體降解系統功能的缺失，因此我們想探討過度表現亨廷頓相關蛋白40對泛素-蛋白酶體降解系統功能的影響，結果發現當HAP40過度表現時會導致泛素-蛋白酶體降解系統失常。另外，亨廷頓相關蛋白40過度表現會促進誘導細胞自噬流量並且也會促進突變型亨廷頓蛋白聚集體形成，在前人研究發現處理rapamycin抑制mTOR以促進細胞自噬時可減少突變型亨廷頓蛋白聚集體數目，因此我們在亨廷頓相關蛋白40過度表現的情況下再加入rapamycin，發現聚集體數目明顯減少。文獻指出當HDAC6受抑制時，會提高微管運動蛋白和微管之間的親和性，並加速物質在微管上的運輸，並且HDAC6參與在清除泛素化蛋白的過程中，因此我們也探討在亨廷頓相關蛋白40過度表現的情形下再加入tubastatin A對聚集體數目的影響，結果發現聚集體數目明顯減少。由於目前為止對亨廷頓相關蛋白40的功能了解的不多，所以我們想藉由探討亨廷頓相關蛋白40會與哪些蛋白質交互作用以釐清其在亨廷頓舞蹈症中扮演的角色，結果得知亨廷頓相關蛋白40可能利用完整的胺基酸片段和亨廷頓蛋白結合，但尚未發現其未與其他蛋白質交互作用。此外我們發現HAP40的NH2及COOH兩端皆會促進聚集體的形成。綜合以上結果顯示過度表現HAP40會造成泛素-蛋白酶體降解系統功能失常，其次rapamycin及tubastatin A可減少因過度表現HAP40而增加的突變型亨廷頓蛋白聚集體數目，此外HAP40需要以完整的胺基酸片段與亨廷頓蛋白交互作用，而HAP40兩端皆會促進聚集體形成，然而目前為止我們尚未發現能與HAP40交互作用的未知蛋白。

Accumulation of mutant huntingtin aggregates in the brain tissues of HD patients and transgenic mouse is a hallmark of Huntington’s disease. Although it is unclear that the mutant huntingtin aggregates is toxic or beneficial for neuronal cells, the accumulation of aggregates in cortical and striatal neurons leads to neuropathological features. Ubiquitin-proteasome system (UPS) is responsible for clearing misfolded proteins. We next aimed to assess the role of HAP40 overexpression on UPS. Results revealed that HAP40 overexpression caused accumulation of UbG76V-GFP, indicating an impairment of UPS. Our previous studies showed that HAP40 overexpression induced autophagic flux by an mTOR-independent manner and promoted mutant huntingtin aggregates formation. Inhibition of mTOR by rapamycin activates autophagy. Therefore, we wondered effect of rapamycin treatment on amount of mutant huntingtin aggregates induced by HAP40 overexpression. Results showed that amount of aggregates decreased upon rapamycin treatment. The aggresome pathway coordinated by HDAC6 is activated when proteasomal functions are impaired. Inhibition of HDAC6 deacetylase activity increases tubulin acetylation and promotes the recruitment of motor proteins to microtubules. Hence, we wondered how treatment of tubastatin A modulated HAP40-induced mutant huntingtin aggregates formation. Results demonstrated that tubastatin A was able to reduce amount of aggregates. Since the function of HAP40 is largely unclear, we then identified proteins that interact with HAP40. We found that HAP40 interacts with huntingtin but the interaction of HAP40 with other proteins has not yet been found.

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