脊髓小腦運動失調症(Spinocerebellar ataxias, SCAs)為一群體染色體顯性遺傳的神經退化性疾病，大部分亞型肇因於基因中的重複片段異常擴增所致。病人主要的臨床症狀有步伐不穩、肢體障礙、癡呆、癲癇等，在病理上則有明顯的小腦萎縮及神經細胞退化等現象。第十七型脊髓小腦運動失調症(SCA17)主要致病原因為TATA-box binding protein (TBP)基因5’端之CAG/CAA三核苷重複過度擴增所引起，產生N端帶有過度擴增多麩胺酸(polyglutamine, polyQ)的TBP蛋白，這種帶有polyQ過度擴增的蛋白會傾向在細胞內形成不溶解的聚集物(insoluble aggregate)，進而慢慢地影響神經細胞的活性，最後導致神經細胞死亡。目前臨床上多半使用藥物減緩該疾病症狀，但並無合適的藥物可以治療。因此本論文研究我們建立小腦組織的初級細胞培養，並利用此系統進行疾病的早期病理分析與潛力藥物的篩選。我們參照前人文獻並加以修改，成功的建立小腦的初級細胞培養系統，根據實驗結果顯示，此方法可以維持大量神經細胞長時間存活並且減低神經膠細胞的過度增生。利用此系統我們分析了Purkinje cell在型態上的差異，發現疾病細胞確實會隨著時間而出現明顯的退化。除此之外，我們也發現在此系統中，同樣亦可看到Purkinje cell隨著培養時間增長而表現累積的錯誤折疊蛋白，但出現大量錯誤折疊蛋白的時間晚於型態的退化，因此我們認為此病徵可能是疾病晚期的現象，但可能不是造成疾病開始出現退化的原因。由上述結果顯示此平台確實可以模擬活體動物所看到的退化病徵。同時我們利用白血球生長激素 (granulocyte colony-stimulating factor)評估本細胞平台是否可應用於SCA17潛力藥物篩選並確認此細胞平台確實可以有效評估藥物效果。因此我們利用此平台測試了許多中草藥並篩選出NH-003及NH-015兩種潛力藥物。總結本研究結果，我們成功的建立了SCA17小腦初級細胞培養並且確認此平台可以作為SCA17病理機制研究與潛力藥物篩選。

Spinocerebellar ataxia (SCA) is a complex group of heterogeneous autosomal dominant neurodegenerative disease. The main clinical symptoms in patients consist of ataxia, dystonia, parkinsonism, dementia and seizures, and with a significant cerebellum atrophy in pathology. Many SCAs are caused by the trinucleotide expansion of disease-causing genes. Spinocerebellar ataxia type 17 (SCA17) is resulted from CAG repeat expansion of TBP gene, which encodes polyglutamine (polyQ) stretch in mutant TBP protein. Pathological studies have observed neuron loss in cerebella of patients and hTBP transgenic mice. To study the early pathogenesis and screen potential Chinese herbs for SCA17, we have established a primary culture system from the transgenic mouse cerebella. In the cerebellar primary culture, we observed approximately 70% NeuN positive cells after a long-term culture. That IP3R1 and calbindin positive cells were sustained, revealing this culture system could maintain Purkinje cells survived for more than 4 weeks in vitro. Furthermore, we found that the neurites undergo processing during the culture period, and the reduced processing of SCA17 primary culture can be identified compared to wild-type culture in 6 parameters. In line with expectations, no degenerative cells were observed after 5 days in vitro, however, significant degeneration could be identified in transgenic culture after 14 and 21 days. In addition, severe aggregation was formed in SCA17 primary culture at day 21, which was later than the neurite degeneration. We suggest that aggregation may not an initial event but a late stage symptom of degeneration. We further applied G-CSF to this primary culture to confirm that this system was an appropriate platform for drug screening. Finally, with this culture system, we have evaluated several Chinese herbs and found NH-003 and NH-015 could be potential in neuronal protection. In summary, we have established the SCA17 cerebellar primary culture and which could be a system to study the pathogenesis and screen potential treatments for SCA17.

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