聚麩醯胺(polyQ)介導的脊髓性小腦共濟失調(SCA)是由編碼polyQ束的CAG三核苷酸重複序列異常擴增引起的異質性退化性疾病。錯誤折疊和聚集的polyQ蛋白是polyQ疾病的一個共同特徵，會導致神經元功能障礙和退化。在SCA中，第三型脊髓性小腦共濟失調症(SCA3)是全球最常見的形式。SCA3的特點是染色體14q32.1上ATXN3基因的CAG重複擴增，在正常個體中重複次數為10至44次，在大多數臨床診斷患者中則重複61至87次。由於擴增的polyQ蛋白的積累可能是致病性的初始事件，因此通過自噬清除聚集蛋白，被認為可以抑制廣泛的下游有害作用，以促進神經細胞存活。因此，本研究旨在尋找可以通過激活自噬作用來清除聚集的ATXN3/Q75的潛在化合物。共測試了10種化合物，包括5種吲哚衍生物和5種香豆素衍生物。其中，吲哚衍生物NC009-1、-2、-6和香豆素衍生物LM-031在Thioflavin T結合和點印跡分析中，會抑制大腸桿菌衍生的ATXN3/Q75蛋白聚集。使用誘導DsRed-LC3表達的HEK-293螢光報告細胞，發現NC009-2、-3和LM-031的處理顯著誘導了DsRed-LC3向自噬體的募集。在ATXN3/Q75-GFP SH-SY5Y細胞中，與未處理的細胞相比，NC009-1、-2、-6和LM-031顯示出良好的聚集抑制潛力，及改善神經突生長，而NC009-1、3、6和LM-031降低ATXN3/Q75蛋白表達後上升的活性氧化物。NC009-1、-2、-6和LM-031通過增加細胞中磷脂醯乙醇胺(PE)偶聯的LC3-II/細胞質LC3-I的比率來啟動自噬。該研究結果可能提供polyQ介導的疾病治療策略的參考。

關鍵詞：第三型脊髓性小腦共濟失調症、聚麩醯胺、ATXN3、自噬作用

Polyglutamine (polyQ)-mediated spinocerebellar ataxias (SCA) are heterogeneous degenerative diseases caused by abnormal expansion of CAG trinucleotide repeats encoding polyQ tracts. The misfolded and aggregated polyQ proteins, a common feature of polyQ disease, lead to neuronal dysfunction and degeneration. Among SCA, spinocerebellar ataxia type 3 (SCA3) is the most common form worldwide. It is characterized by CAG repeat expansion of the ATXN3 gene on chromosome 14q32.1, which is repeated 10 to 44 times in normal individuals and 61 to 87 times in most clinically diagnosed patients. As accumulation of expanded polyQ proteins may be an initial event for pathogenicity, clearance of aggregated proteins by autophagy is thought to suppress a wide range of downstream deleterious effects to promote neuronal survival. Therefore, this study aimed to search for potential compounds that could clear aggregated ATXN3/Q75 by activating autophagy. A total of 10 compounds were tested, including 5 indole derivatives and 5 coumarin derivatives. Among them, indole derivatives NC009-1, -2, -6, and coumarin derivative LM-031 interfered with E. coli-derived ATXN3/Q75 protein aggregation in Thioflavin T binding and dot blot assays. Using 293-based fluorescent reporter cells with induced DsRed-LC3 expression, treatment of NC009-2, -3 and LM-031 significantly induced the recruitment of DsRed-LC3 to autophagic vacuoles. In ATXN3/Q75-GFP SH-SY5Y cells, NC009-1, -2, -6 and LM-031 displayed good aggregation-inhibitory and neurite growth promoting potentials compared with untreated cells, while NC009-1, -3, 6 and LM-031 reduced reactive oxygen species production in response to ATXN3/Q75-GFP expression. NC009-1, -2, -6 and LM-031 activated autophagy by increased phosphatidylethanolamine (PE)-conjugated LC3-II/cytosolic LC3-I ratio in these cells. The study results may provide a reference for the treatment strategy of polyQ-mediated diseases.

Keywords: Spinocerebellar ataxia type 3 (SCA3), Polyglutamine, ATXN3, Autophagy

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