亨廷頓舞蹈症是一種顯性遺傳的神經退化性疾病，造成疾病的主因是亨廷頓蛋白基因發生突變，導致亨廷頓蛋白的多聚麩醯胺過度擴張，最後因異常的蛋白質堆積使得腦部神經細胞死亡。亨廷頓蛋白參與許多細胞內的調控，包含微管軸突的運輸，其功能會受到與亨廷頓結合蛋白和亨廷頓相關蛋白相互作用而影響，亨廷頓相關蛋白40與微管有相互作用，另外與亨廷頓蛋白可以直接結合，影響早期內噬體對細胞骨架親和性，調節其運輸；此外在亨廷頓舞蹈症模式小鼠的紋狀體細胞以及患者腦部組織中內生性亨廷頓相關蛋白40蛋白大量表現。因此，本篇的研究目的主要是想要探討亨廷頓相關蛋白40是否參與亨廷頓舞蹈症致病機轉以及其他細胞功能的調控。結果發現過量表現亨廷頓相關蛋白40促使由突變型亨廷頓蛋白形成聚集體的數目增加，且有形成聚集體的小鼠神經母細胞瘤細胞增多。進一步了解聚集體增加是否因蛋白質降解作用損害，結果顯示亨廷頓相關蛋白40過量表現使得泛素化蛋白質增加，且由離胺酸48形成的多泛素鏈累積，此外也發現內生性p62蛋白量和p62 的點狀數目都有增加的現象。亨廷頓相關蛋白40表現也造成高基氏體的結構較擴散。在小鼠神經母細胞瘤細胞株和大鼠腎上腺嗜鉻細胞瘤細胞株的細胞穩定株誘導亨廷頓相關蛋白40表現促使有神經軸索生長的細胞增加。綜合以上結果指出，亨廷頓相關蛋白40促進突變型亨廷頓蛋白的聚集體形成，並促使泛素化蛋白的堆積，另外亨廷頓相關蛋白40表現使得高基氏體的型態改變，進一步推測可能影響神經軸索生長。

Huntington's disease (HD) is a dominant inherited neurodegenerative disorder caused by CAG repeats encoding polyglutamine (polyQ) expansion within the first exon of huntingtin (htt). The amino-terminal fragments of mutant huntingtin accumulate and form aggregates in neuronal nuclei and cytoplasm, primarily in the striatum and cortex of HD patients. It is still unclear whether aggregates are protective or detrimental for cell viability. Htt is enriched in the brain where it associates with microtubules and vesicles, such as Golgi apparatus, and mitochondria. HAP40 is a 40-kDa huntingtin-associated protein. Like huntingtin, HAP40 associates with microtubules and shuttles in axon. Previous studies have shown the huntingtin–HAP40 complex is an effector of Rab5 that regulates the dynamics of early endosomes through a switch from microtubules to F-actin. Endogenous HAP40 protein levels were increased in STHdhQ111 striatal cells and fibroblasts and brain tissue from human HD patients. Thus, up-regulation of HAP40 protein level might contribute to the selective neuropathology of HD. Previous studies had shown that aggregates of mutant N-Htt are enriched for components of the protein quality control machinery, such as ubiquitin, proteasome subunits, and chaperones. We found that overexpression of HAP40 promotes aggregation of mutant huntingtin in N2a cell. To investigate whether HAP40 affects ubiquitin proteasome system, we transfected N2a cell with HAP40, ubiquitin and N-Htt (WT or mutant). Overexpression of HAP40 enhances accumulation of polyubiquitinated protein. Depletion of Htt in HeLa cells results in Golgi disruption, similar to the effects by depletion of dynein and dynactin. In stable N2a cell lines expressing HAP40, the structures of Golgi were disrupted. During neurite outgrowth, actin and microtubules dynamics and membrane traffic play a role in initiation and elongation of neurites. In PC12 and N2a stable cell lines expressing HAP40, we found that HAP40 increase the percentage of cells with neurite.

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