脊髓小腦共濟失調症第三型（Spinocerebellar ataxia ，簡稱 SCA3），為罕見顯性遺傳神經退化性疾病，主因為突變的 ataxin 3 蛋白（ATXN3）形成不可被降解的聚麩胺醯酸（polyQ）片段，此片段堆疊後具毒性並異常積累於小腦，使得神經元凋亡，最後導致人體肌肉不協調並呼吸衰竭而死亡。全世界的SCA患者超過半數為第三型，現無任何有效的治癒方法，僅能利用物理方式或少數藥物減緩疾病之惡化。目前藥物開發之策略主要為保護神經元或減少異常聚集之毒性片段。本研究利用 SCA3 動物及細胞模型探討 TSCA-001 藥物將毒性片段清除之機制，以了解延緩疾病惡化與改善 SCA3 之原因。在SCA3小鼠發病後口服TSCA-001藥物5週 (每天 2 次 )，透過旋轉棒性能測試和步態分析，發現SCA3 小鼠運動協調行為有顯著的改善。此外，利用共軛焦顯微鏡與免疫螢光染色分析SCA3 小鼠之小腦，發現 TSCA-001 可維持小腦內浦肯野細胞的樹突和完整性，以及減少毒性片段蛋白質-突變 ATXN3 和 polyQ 的異常堆積現象；西方點墨法結果指出，TSCA-001增強浦肯野細胞之自噬途徑標的蛋白質[ beclin 1（BECN1）與 light-chain-3B-II（LC3B-II）]，並減少毒性片段的堆積。另一方面，在 HEK-293GFP-ATXN3-84Q 中，亦可證實與再現TSCA-001 通過增強自噬路徑，即提升基因 autophagy-associated protein 3 （ATG3）、 ATG7 和標的蛋白質 BECN1 與 LC3B 之表現，使毒性堆積蛋白因此減少。我為了更深入分析 TSCA-001於自噬路徑中作用時機與機制，故使用抑制劑 wortmannin 與 bafA1 剖析自噬途徑的階段性。在西方點墨法分析，發現兩種抑制劑於有效活性期間阻斷了 TSCA-001 在自噬路徑之初始階段活化能力，因此毒性堆積蛋白無法被分解且持續累積。綜上所述，本研究發現 TSCA-001 活化自噬路徑之上游 mTOR/ PI3K-AKT 訊息，促進自噬路徑以清除 polyQ 堆積，使 Purkinje cell 死亡減少，進而顯著改善了 SCA3 小鼠之運動協調性，故 TSCA-001 作為治療 SCA3 極具潛力。

Spinocerebellar ataxia type 3 (SCA3), a rare hereditary neurodegenerative disease, is profoundly attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin 3 gene (ATXN3). The toxic fragments processed from mutant ATXN3 can induce the death in neurons and it leads to the muscular incoordination of the human body. Some treatment strategies of SCA3 are preferentially focusing on ameliorating the neurons or depleting the abnormal aggregates. In this study, I report that TSCA-001 could protect the dendrites of Purkinje cells from fragmentation and promote the elimination of toxic aggregates to ameliorate the motor deficits in vivo. During the treatment in vivo, the behaviors of SCA3 mice exhibited significant improvements, as measured by the rotarod performance test and footprint pattern analysis. The representative confocal microscopic images and Western blotting analysis of the SCA3 cerebellum suggested that TSCA-001 could not only maintain the dendrites and integrity of Purkinje cells, but also enhance the autophagy-associated protein, beclin 1 (BECN1) and light-chain-3B-II (LC3B-II), to remove the mutant ATXN3 and polyQ. On the other hand, in HEK293GFP-ATXN3-84Q, TSCA-001 depleted the aggregates by enhancing the autophagy-related players, i.e. autophagy-related protein 3 (ATG3), ATG7, and both the gene and protein expression of BECN1 and LC3B-II. To reveal the crucial role of TSCA-001, I applied two autophagy inhibitors for dissecting each stage of the autophagic pathway. The Western blotting analysis indicated the wortmannin and bafA1 blocked the effect of TSCA-001 on the initial phase of autophagy. To sum up, this study uncovers the role of TSCA-001 in the upstream of autophagy, mTOR/PI3K-AKT signaling, and this can be a promising therapy for SCA3.

Acknowledgements III
摘要 V
Abstract VII
Table of Contents IX
List of figures XII
List of tables XIV
Abbreviations 1
1. Introduction 3
1.1 Spinocerebellar ataxia (SCA) 3
1.2 Spinocerebellar ataxia type 3 (SCA3) 3
1.2.1 Cerebellum 4
1.2.2 Purkinje cells 5
1.2.3 ATXN3 6
1.2.4 Toxic fragment 7
1.2.5 Treatments for SCA3 8
1.3 Protein degradation 9
1.3.1 Proteasome pathway 11
1.3.2 Autophagy 12
1.3.2.1 Initiation 12
1.3.2.2 Nucleation 13
1.3.2.3 Elongation 13
1.3.2.4 Maturation 13
1.4 TSCA-001 15
2. Aims 17
3. Materials and Methods 19
3.1 Experimental process design 19
3.1.1 In vivo 19
3.1.2 In vitro 20
3.2 In vivo experiments. 20
3.2.1 Animals and treatments 20
3.2.2 Behaviour assays 21
3.2.2.1 Rotarod performance 21
3.2.2.2 Footprint pattern 22
3.3 Immunofluorescence (IF) staining 22
3.4 Western blotting analysis 23
3.4.1 Protein isolation and quantification 23
3.4.2 SDS-PAGE analysis 23
3.5 In vitro experiments. 25
3.5.1 Cell culture 25
3.5.2 Cell treatments 25
3.6 Preparation of quantitative real-time PCR 26
3.6.1 RNA isolation and quantification 26
3.6.2 Reverse-transcription PCR 26
3.6.3 Quantitative Real-time PCR 26
3.7 Statistical analysis 27
4. Results 29
4.1 TSCA-001 largely improves motor incoordination in SCA3 mice. 29
4.2 TSCA-001 ameliorates neuropathology in SCA3 mice through the neuroprotection of Purkinje cell’s integrity and the decreases of toxic fragments in the cerebellum. 30
4.3 TSCA-001 treatment activates autophagy to eliminate toxic aggregates in vivo and in vitro. 31
4.4 TSCA-001 modulates the autophagic pathway in the initiation phase. 32
4.5 TSCA-001 regulates the upstream signaling of autophagy. 33
5. Discussion 50
6. Conclusion 52
7. Reference 53

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