在神經細胞中，運動蛋白藉由在軸突的微管上運送囊泡，包括與驅動蛋白進行正向而與動力蛋白進行反向運輸來進行訊號傳遞。當軸突運輸遭到破壞之後常會導致一些神經疾病，例如亨廷頓舞蹈症。先前研究指出亨廷頓蛋白會藉由跟亨廷頓相關蛋白1與40結合，在微管上進行運輸，例如：亨廷頓蛋白跟亨廷頓相關蛋白1結合，在微管上進行正向及反向運輸。而亨廷頓相關蛋白40也調節小鳥糞嘌呤核苷三磷酸酵素招引亨廷頓蛋白至早期內噬體，並使早期內噬體從微管轉至肌動蛋白運輸。因此本篇論文主要在探討微管相關蛋白如：亨廷頓蛋白、亨廷頓相關蛋白1與亨廷頓相關蛋白40對小鼠神經母細胞瘤細胞株的生存能力、突變亨廷頓蛋白聚集的情況以及聚集體形成的狀態有什麼影響。首先利用小髮夾型核醣核酸來降低蛋白的表現量，發現當亨廷頓蛋白表現降低時，內生性亨廷頓相關蛋白40的表現量也下降；而在亨廷頓相關蛋白40減少的情況下，內生性亨廷頓蛋白的表現量也降低；但在降低亨廷頓相關蛋白1表現時，亨廷頓蛋白及亨廷頓相關蛋白40的表現不受影響。接著探討細胞的存活率，發現降低亨廷頓蛋白與亨廷頓相關蛋白1表現細胞存活率會增加，過度表現亨廷頓相關蛋白1則會減少，而降低亨廷頓相關蛋白40的表現細胞生存能力也隨之降低。文獻指出，在亨廷頓舞蹈症患者大腦的皮質與紋狀體中，突變亨廷頓蛋白會聚集在神經細胞核，我們進一步了解亨廷頓蛋白、亨廷頓相關蛋白1與亨廷頓相關蛋白40對突變亨廷頓蛋白聚集的形成的影響。發現降低亨廷頓蛋白與亨廷頓相關蛋白1表現會使突變亨廷頓蛋白聚集增加，過度表現亨廷頓相關蛋白1與降低亨廷頓相關蛋白40表現則突變亨廷頓蛋白聚集不受影響。亦有文獻指出，當泛素-蛋白酶系統降解突變亨廷頓蛋白的能力衰弱之後，就會使得聚集體產生。因此想瞭解亨廷頓相關蛋白1與亨廷頓相關蛋白40是否有參與在內，發現突變亨廷頓蛋白的確有參與在聚集體中，並且經由蛋白酶體抑制劑誘導產生的聚集體，亨廷頓相關蛋白1A與亨廷頓相關蛋白40也參與在內。綜合以上結果顯示出亨廷頓蛋白與亨廷頓相關蛋白1若被削弱，突變亨廷頓蛋白的聚集就很容易形成，影響細胞對錯誤折疊蛋白的清除，而亨廷頓相關蛋白1A和亨廷頓相關蛋白40可能參與聚集體的形成，進而保護由具有麩醯胺酸重覆序列的細胞所產生的毒性。

Transport of vesicles in neurons is a highly regulated process, with vesicles moving either anterogradely or retrogradely depending on the nature of the molecular motors, kinesins and dynein. The neurodegenerative disorder Huntington’s disease is caused by an expansion in the polyglutamine repeat region of the protein huntingtin. Htt protein regulates transport of endocytic vesicles by interacting with trafficking adaptors such as huntingtin-associated protein 1 and 40 (HAP1 and HAP40). HAP1 is interacts with dynactin p150Glued (dynactin p150) and kinesin light chain (KLC). HAP40 shifts early endosome from microtubule to actin filament via recruitment of Htt by Rab5. Previous studies show that dynein dysfunction increases aggregate formation in mouse model of Huntington’s disease. Thus, we investigated the effects of HAP1 and HAP40 on cell viability and aggresome formation. We studied the function of HAP1 and HAP40 by knocking down their expression with shRNAs in mouse neuroblastoma cells (N2a cells). Western blot assays showed that, after reduction of HAP40, endogenous Htt level was decreased. Similarly, endogenous HAP40 level was lower after a reduction of Htt. Our previous data showed that overexpression of HAP40 reduces cell viability. Here, MTT assay showed that loss of HAP40 also reduced cell viability. On the other hand, loss of HAP1 increased cell viability, while overexpression of HAP1 reduced cell viability. Furthermore, loss of HAP1 promoted aggregates formation of mutant huntingtin QP103-GFP. Overexpression of HAP1 did not affect aggregates formation of mutant huntingtin. Our previous study showed that overexpression of HAP40 promotes aggregates formation of mutant huntingtin. We found that loss of endogenous HAP40 did not affect aggregates formation of mutant huntingtin significantly. Aggresomes are inclusion bodies that form when the ubiquitin–proteasome machinery is overwhelmed with aggregation-prone proteins. We found that HAP1A and HAP40 colocalized with aggresome after MG132 treatment. This may affect the clearance of misfolded proteins in N2a cells.

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