摘要

脊髓小腦共濟失調症(SCA)為一群神經退化性疾病，其主要特徵為小腦功能異常，有時也會出現其他神經異常情況，其中第二型及十七型SCA (SCA2、SCA17)和蛋白轉譯區CAG三酸重複擴增相關。SCA17致病基因位於染色體6q27位置，其產物為轉譯起始因子TATA binding protein (TBP)。本研究利用基因型分析(genotyping)技術，首先分析台灣地區包括正常人族群、運動失調症患者、PD患者、AD患者、精神病患者及其他神經疾病族群SCA2、SCA17基因CAG重複範圍，結果於SCA2中發現1個位於正常及擴增範圍邊界的對偶基因(32個重複)，及4個擴增的致病對偶基因(35、40、48及49重複)，於SCA17中則未發現擴增的致病對偶基因，但觀察到5個邊界的對偶基因(44~46重複)。為了了解致病機轉，本研究建立了正常人及SCA17病人的EBV轉型淋巴細胞，並架構了包含 3~61 CAG三核重複的 TBP cDNA，表現於SK-N-SK細胞，利用氧化劑t-butylhydroperoxide (TBH)來檢測這些表現正常與擴增CAG三核重複的細胞對氧化壓力的忍受度。細胞存活及SOD活性定量結果顯示，與表現正常TBP基因的細胞相較，表現擴增TBP基因的細胞對於氧化壓力的忍受度會下降。利用定量蛋白體學方法，比較正常人及SCA17病人淋巴細胞的蛋白表現，初步結果發現一些熱休克蛋白及氧化壓力相關蛋白表現的變異。

Abstract

Spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders characterized by cerebellar dysfunction alone or in combination with other neurological abnormalities. Among them, both SCA2 and SCA17 were caused by the expansions of coded CAG trinucleotide repeats. The chromosome 6q27 SCA17 gene encodes a transcription initiation factor TATA-box binding protein (TBP). In this study, SCA2 and SCA17 genotyping was performed to set up the repeat size range in Taiwanese control subjects and in patients with ataxia, dementia, PD, schizophrenia, and other neurological disorders. For SCA2, one borderline (32 repeats) and four pathogenic (35, 40, 48, and 49 repeats) alleles were observed in patients group. For SCA17, no pathogenic expansion was found, but five borderline alleles (44~46 repeats) were found in patients group. To investigate the pathogenic mechanisms underlying the disease, EBV-transformed lymphoblastoid cells from controls and patients with SCA17 TBP expansions were established. Constructs with 3~61 CAG repeat-containing TBP cDNA were also prepared and expressed in SK-N-SK cells to assess the oxidative tolerance of cells upon exposure to t-butylhydroperoxide (TBH). By quantifying the cell viability and the amount of SOD upon TBH treatment, the cells expressed expanded TBP were shown to be more vulnerable to TBH than the cells expressed normal TBP. Quantitative proteomics was used to compare the overall protein expressions among lymphoblastoid cells from SCA17 patients and normal controls. So far, some heat shock factors and oxidative stress related proteins have been suggested from the peer results.

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