Author: |
孫定中 Ting-Chung Sun |
---|---|
Thesis Title: |
以SCA17小鼠系統評估對於polyQ疾病有潛力的HDAC抑制劑 Identification of Potential HDAC Inhibitor Compounds for PolyQ Diseases with SCA17 Mouse System |
Advisor: |
謝秀梅
Hsieh, Hsiu-Mei |
Degree: |
碩士 Master |
Department: |
生命科學系 Department of Life Science |
Thesis Publication Year: | 2014 |
Academic Year: | 102 |
Language: | 中文 |
Number of pages: | 81 |
Keywords (in Chinese): | 第17型脊髓小腦萎縮症 、基因轉殖鼠 、小腦初級培養 、組織蛋白去乙醯酶抑制劑 |
Keywords (in English): | SCA17, HDACi, NC105, NC109 |
Thesis Type: | Academic thesis/ dissertation |
Reference times: | Clicks: 144 Downloads: 1 |
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脊髓小腦萎縮症(Spinocerebellar ataxia, SCA),是群異質性體染色體顯性遺傳的神經退化性疾病,主要病徵包括共濟失調、癡呆、肌張力障礙及癲癇等,病理特徵主要是小腦萎縮。第17型脊髓小腦萎縮症(SCA17)是由於在TATA-binding protein (TBP)基因上有過度重複擴增的CAG/CAA序列重複所引起的一種多麩醯胺酸(polyglutamine, polyQ)疾病,TBP是三種RNA聚合酶轉錄起始的重要轉錄因子,多麩醯胺酸過長造成蛋白質錯誤折疊而堆積,並進而引發細胞損傷及退化,尤其以小腦的Purkinje cell特別明顯。組織蛋白去乙醯酶(Histone deacetylase, HDAC)會將組蛋白之乙醯基團移除而讓組蛋白更緊密的與DNA結合,抑制基因的轉錄,造成許多疾病,組織蛋白去乙醯酶抑制劑(HDACi)可以改善轉錄的抑制,並在一些神經退化性疾病中扮演神經保護的角色,我們建立SCA17小鼠小腦的初級細胞培養和小腦切片培養來篩選HDACi,並將有潛力的化合物進行動物行為實驗。在SCA17小鼠小腦的初級細胞培養中我們發現NC105和NC109可以增加Purkinje cell的神經突生長(neurite length),在SCA17小鼠小腦的體外切片培養也看到TBP聚集有明顯的下降,因此用NC105和NC109進行小量動物行為的預試驗,我們發現SCA17小鼠的體重並沒有明顯受到藥物之改變,運動平衡改善上,NC105和NC109組別的小鼠在rotarod停留的時間有增加的趨勢,病理上我們發現SCA17小鼠Purkinje cell退化情形有得到改善,同時Histon H3與Histon H4乙醯化程度有明顯提高,我們也發現給予NC105和NC109的SCA17小鼠Purkinje cell TBP聚集的情形有明顯改善,因此我們認為NC105和NC109能抑制HDAC以改善轉錄的異常。進入了大量動物行為實驗之後,NC105及NC109之處理並不影響小鼠體重,也不影響小鼠的焦慮,但改善小鼠的運動協調能力,同時增加HSP的表現,NC109更能有效降低TBP不正常聚集,因此我們認為NC105和NC109是有潛力改善SCA17小鼠病徵的HDACi。
Spinocerebellar ataxia (SCA) is a group of heterogeneous autosomal dominant neurodegenerative diseases. Clinical symptoms include ataxia, dementia, dystonia, seizures, and significant cerebellum atrophy in pathology. Spinocerebellar ataxia type 17 (SCA17) is one type of SCAs. It is caused by CAA/CAG repeat segment of the TATA-binding protein (TBP) gene. TBP is a crucial transcription factors for all the three RNA polymerase in transcription initiation. The polyglutamine (polyQ)-expanded mutant TBP accumulates as aggregates in the cells and leads to cell degeneration, especially the cerebellar Purkinje neurons. Histone deacetylases (HDAC) make the histones more tightly bind to DNA by removing the acetyl groups from histones, which in turn suppresses the gene transcription and causes many diseases. HDAC inhibitors could alleviate transcription suppression and show neuroprotecive effect in several neurodegenerative diseases. We used the mouse cerebellar primary culture from the SCA17 transgenic mice established in our lab to screen HDAC inhibitors. The potential compounds were further applied for in vivo test. We found two HDAC inhibitors, NC105 and NC109, can increase Purkinje cell total neurite lengthon primary culture and decrease TBP aggregation on slice culture. These two HDAC inhibitors were applied to small-scale SCA17 mice to verify their efficacy in vivo. During the in vivo treatment, mouse body weight was not altered by HDACi treatment. In addition, mouse motor coordination was improved from the rotarod task evaluation. Our preliminary results show these two inhibitors alleviate Purkinje cell degeneration and increase histone acetylation. NC105 and NC109 treatment can also decrease TBP aggregation. These compounds might alleviate the transcriptional dysfunction of SCA17 through inhibition of HDAC. These two HDAC inhibitors also could significant improved mouse motor coordination from the behavior evaluation for large scale animal test. In sum, NC105 and NC109 show significant effect in vitro and improve motor coordination and reduce neuron degeneration of SCA17 transgenic mice. The result suggests that these two HDACi could be potential HDAC inhibitors for SCA17 treatment.
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