臺灣博碩士論文加值系統

漢丁頓舞蹈症肇因於huntingtin 基因第一個表現子上的CAG核酸重複片段的過度增長。大腦皮質與基底核中的紋狀體為最主要受影響的區域。近年來有許多文獻指出，漢丁頓舞蹈症具有能量代謝異常的現象，但其中的機制則尚未明瞭。利用二維膠體電泳，我們發現在R6/2漢丁頓舞蹈症小鼠模型中，紋狀體內的腦型核酸肌酸酶表達量受抑制的現象。已知腦型核酸肌酸酶可透過催化肌酸以及磷酸化肌酸之間的轉換，放出ATP能量，提供細胞內特殊區域中能量的消費利用。利用定量反轉錄聚合酶連鎖反應分析，以及啟動子活性分析，我們發覺腦型核酸肌酸基因的轉錄受到突變型漢丁頓蛋白(htt109Q)的抑制。免疫細胞染色指出腦型核酸肌酸酶可廣泛表達在神經元細胞本體，以及神經突出上。更有趣的是，R6/2小鼠神經突出上的核酸肌酸酶則顯著減少了。外源性表達腦型核酸肌酸酶可拯救突變漢丁頓蛋白所造成的異常，包括:細胞存活率的下降，突變漢丁頓蛋白的聚集，以及神經突起生長受損的現象。我們發現直接利用核酸肌酸酶的短髮夾核醣核酸(shRNA)來抑制Neuro-2a細胞中的腦型核酸肌酸酶亦會抑制神經突起的生長。我們的研究認為，腦型核酸肌酸酶的降低，對於漢丁頓舞蹈症神經功能異常扮演重要的角色，利用增加腦型核酸肌酸酶的活性或表達量，將可能是改善漢丁頓氏症的重要標的。
本論文的第二部分，則是探討漢丁頓氏症病患的聽力喪失問題，以及與腦型磷酸肌酸酶的相關性。過去的研究曾指出，腦型磷酸肌酸酶在聽覺毛細胞中的絨毛扮演重要的能量維持與傳遞的角色，我因此探討漢丁頓舞蹈症病人是否有聽力缺損。本研究共蒐集了十九位漢丁頓舞蹈症的病患(年齡在四十到五十九歲之間)，進行純音聽力檢查(PTA)以及聽性腦幹反應檢查。漢丁頓舞蹈症的病患純音聽力檢查的閥值具有顯著增加的情形。與臨床的發現一致，利用兩種不同的漢丁頓舞蹈症小鼠模型(R6/2 and Hdh(CAG)150) 聽性腦幹反應的閾值也顯著提高。這些證據證明罹患漢丁頓氏症會引發聽力喪失。免疫組織染色指出突變型huntingin亦可在耳蝸中表現，並形成核內聚集體影響其正常功能。定量反轉錄聚合酶連鎖反應及西方式點墨亦指出漢丁頓小鼠耳鍋中腦型核酸肌酸酶表達量的降低。利用補充肌酸，漢丁頓小鼠的聽力損傷受到顯著的改善，磷酸化肌酸及腦型核酸肌酸酶系統功能在漢丁頓氏症可能受損，進而使得聽力受損。最重要的，利用肌酸可改善漢丁頓氏症的聽力受損。
綜論以上發現腦型核酸肌酸酶的減少，無論在中樞神經系統，以及週邊感覺神經皆扮演重要的角色，研究如何增強病患腦型核酸肌酸酶的活性或蛋白表達，將可能是治療漢丁頓舞蹈症的新標的。

Huntington’s disease (HD) is caused by expended CAG repeat in the exon 1 of huntingtin gene, and preferentially affects the functions of the striatum and cortex in the brain. Recent studies indicate that energy metabolism is impaired in HD, but the mechanisms remain unclear. Using 2D gel electrophoresis, we found that brain type creatine kinase (CKB) was down-regulated in the striatum of a transgenic HD mouse model (R6/2). The major function of CKB is known to regenerate ATP through regulating the levels of creatine and phosphor-creatine at specific energy consuming sites. By using a quantitative RT-PCR analysis and the promoter assay, we found that the transcript level of CKB was suppressed by polyglutamine-expanded mutant Huntingtin (Htt). Immunocytochemical staining revealed that CKB existed in both soma and neuronal processes. Interestingly, expression of CKB protein in the neuronal processes of R6/2 mice was greatly reduced when compared to those of age-controlled wildtype mice. Exogenous expression of CKB rescued the mutant Htt-induced defects including cell survival, Htt aggregate, and damaged neurite outgrowth. We also showed that down-regulation of CKB in Neuro-2a cells caused inhibition of neurite outgrowth. Our data suggest that downregulation of CKB contributes to neuronal dysfunction in HD. Strategies aimed at increasing the expression or activity of CKB may lead to beneficial effects on the progression of HD.
In the Second part of this thesis, the hearing loss in HD and the associated down regulation of CKB was investigated. We initiated this study because CKB is particularly important in ATP homeostasis in high energy demanding organs, and that CKB knockout mice show significant hearing loss. We hypothesized that CKB down-regulation may also occur in the cochlea and cause hearing defect in HD. In this study, 19 HD patients (aged 40–59) were assessed using pure-tone audiometry (PTA) and auditory brainstem responses (ABR). We demonstrate that the PTA thresholds were significantly elevated in HD patients. Consistently, two HD mouse models (R6/2 and Hdh(CAG)150) also showed elevated ABR thresholds. Hearing loss thus appears to be an authentic symptom of HD. Immunohistochemical analyses demonstrated the presence of mutant Htt in the organ of Corti of HD mice, and might interfere with its normal functions. Quantitative RT-PCR and western blot analyses further revealed reduced expression of CKB in the cochlea of HD mice. Treatment with creatine supplements ameliorated the hearing impairment of HD mice, suggesting that the poor PCr-CK system in the cochlea of HD mice may contribute to their hearing impairment. Most importantly, creatine may be used to treat the hearing abnormality of HD patients.
In summary, down-regulation of CKB plays an important role cross the central and peripheral nervous systems. Enhancement of the activity and/or expression of CKB in HD patients may serve as an important therapeutic means for HD.

Contents
Contents i
List of Tables iii
List of Figures iv
List of Abbreviation vi
Chinese abstract viii
Abstract x
Introduction 1
Huntington’s disease (HD) 1
UHDRS 1
Cell cultures 2
HD fly model 2
HD mouse model 3
HD and energy dysfunction 4
Brain-type creatine kinase (CKB) 4
CKB and neurodegenerative disorders 5
CKB interacting protein 5
HD and sensory system dysfunction 7
CKB and hearing function 8
Materials and Methods 9
Results 22
1.1 Down regulation of CKB in the presence of mutant Htt 22
1.2 CKB was down-regulated in the brain of HD mice in an age-dependent manner. 22
1.3 PolyQ-expanded mutant Huntingtin (Htt) suppressed CKB promoter activity 23
1.4 Overexpression of CKB ameliorated the abnormalities caused by mutant Htt in ST14A cells. 23
1.5 Overexpression of the brain type creatine kinase (CKB) attenuated mutant Htt aggregation 24
1.6 Abnormal distribution of CKB in primary cortical neurons purified from R6/2 mice. 25
1.7 Overexpression of CKB rescued the mutant Htt-induced impairment of neurite outgrowth. 25
1.8 Overexpression of CKB rescued the proteosome activity impaired by mutant Htt. 26
1.9 Overexpression of CKB led to beneficial effects on HD flies 27
2.1 HD patients showed impaired hearing sensitivity 27
2.2 Two mouse models of HD exhibit hearing impairment. 29
2.3 PolyQ-expanded mutant Htt forms intranuclear inclustions in the cochlea. 30
2.4 Scanning electron microscope analysis. 30
2.5 CKB is down-regulated in the cochlea of HD mice. 30
2.6 Energy deplete in the cochlea of HD mice. 31
2.7 Beneficial effects of creatine supplementation on auditory dysfunction in HD mice. 31
Discussion 34
Part I 34
Part II 36
Conclusion and perspectives 41
References 42
Tables and Figures 56
Appendices 103
Paper 112

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