脊髓小腦萎縮症(SCA)為體染色體顯性遺傳之神經退化性疾病，其中第1、2、3、6、7、8、17型SCA及齒狀核紅核蒼白球路易體萎缩症(DRPLA)皆起因於特定基因中CAG三核苷酸不正常擴增，進而轉譯出長鏈的多麩醯胺(PolyQ)蛋白。錯誤摺疊的擴增多麩醯胺蛋白傾向於細胞中形成聚集(Aggregation)，此為多麩醯胺疾病(PolyQ disease)之共同病徵。當神經元內累積過多不可溶之聚集，將導致神經元功能障礙，引發漸進性脊髓小腦共濟失調。第三型脊髓小腦萎縮症(SCA3)於眾多亞型中最為常見，患者因座落於14q32.1的ATXN3基因發生突變而致病，在正常人基因中CAG三核苷酸重複約13~36次，但患者基因中重複次數會高達68~79次。由於突變多麩醯胺蛋白的累積為致病主要始因，故透過調控泛素蛋白酶體系統(Ubiquitin proteasome system)活性，以清除聚集的多麩醯胺蛋白，進而抑制聚集導致的細胞毒性，減少神經元死亡，對治療SCA3具有潛力。先前本實驗室使用SCA3 ATXN/Q75-GFP 293細胞株，對順天堂公司提供的中草藥水萃物進行檢測，篩選出14種具抑制PolyQ聚集效果的中草藥水萃物。本研究接續上述結果，利用泛素蛋白酶體系統表達細胞(GFPu)，經流式細胞儀分析，初步篩選出8種顯著提升蛋白酶體活性之水萃物，並以20S蛋白酶體活性分析及西方轉漬法分析泛素化及GFP蛋白確認之。其次鎖定其中5種中草藥水萃物，利用誘導神經分化的ATXN3/Q75-GFP SH-SY5Y細胞，經分析聚集、神經突生長(Neurite outgrowth)、凋亡蛋白酶3 (Caspase 3)活性、蛋白酶體活性，及ATXN3/Q75-GFP、泛素、Bcl-2、Bax等蛋白表現量，確認中草藥水萃物之神經保護效果。最後針對其中兩種中草藥水萃物之3種活性成分，以GFPu細胞及ATXN3/Q75-GFP SH-SY5Y細胞，分別確認其活化蛋白酶體及神經保護效果。此研究希冀能提供SCA3等多麩醯胺疾病良好的治療策略。

Autosomal dominant spinocerebellar ataxias (SCA) including SCA types 1, 2, 3, 6, 7, 8, 17 and dentatorubropallidoluysian atrophy (DRPLA), are caused by the abnormal expansions of CAG trinucleotide repeats and associated polyglutamine (polyQ) tract. Accumulation of insoluble intracellular deposits containing the aggregated disease proteins is a common feature of polyQ diseases, leading to progressive neuronal dysfunction and subsequent degenerative process. Among SCA, SCA type 3 (SCA3) is the most common form of SCA worldwide. It is characterized by a CAG triplet expansion in the ATXN3 gene on chromosome 14q32.1, with 13~36 repeats in normal individuals and 68~79 repeats in most of the clinically diagnosed patients. As accumulation of the mutated polyQ protein is a possible initial event in the pathogenic cascade, clearance of aggregated protein by ubiquitin proteasome system (UPS) is supposed to inhibit a wide range of downstream detrimental events to suppress neuronal cell death. Previously we used SCA3 ATXN3/Q75-GFP 293 cells to screen Chinese herbal medicine extracts provided by Sun-Ten Pharmaceutical Co. for inhibiting polyQ aggregation. Among the tested extracts, 14 displayed good aggregation-inhibitory potential. In this study the identified 14 extracts were examined for enhancing proteasome activity by flow cytometry analysis of ubiquitin-proteasome reporter cells (GFPu) expressing destabilized fluorescent GFP protein. Among the 14 tested extracts, 8 displayed increased proteasome activity which was confirmed by 20S proteasome activity assay and Western blot analysis of ubiquitinated and fused GFP proteins in GFPu cells. Among them, neuroprotection effects of 5 selected extracts were further confirmed by analyses of polyQ aggregation, neurite outgrowth, caspase 3/proteasome activities, and ATXN3-GFP/
ubiquitin/Bcl-2/Bax protein levels in neuronal differentiated ATXN3/Q75-GFP SH-SY5Y cells. Finally enhancement of proteasome and neuroprotection of 3 active constituents from 2 selected extracts were affirmed in GFPu or ATXN3/Q75 SH-SY5Y cells. This study may have therapeutic applications in polyQ-mediated disorders.

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