脊髓小腦運動失調症（SCAs）為一群顯性遺傳的神經退化性疾病，目前已確定的各型中，絕大多數是由致病基因中的三核苷酸或五核苷酸重複擴增所致。本論文首先建立了臺灣地區族群的SCAs致病基因之遺傳資料庫，並且檢測尚未確定的病例。在我們的檢測結果中，臺灣SCAs族群當中最多的為SCA3；且臺灣的族群分佈頻率與日本及高加索人群極為相似。此外，我們亦發現五名帕金森氏症患者具有SCA8或是SCA17基因的突變 ，顯示這兩種基因的突變可能以非小腦症狀的表現型來顯現。
SCA8與其他的SCAs不同之處在於其雖然也是由三核苷酸重複擴增所造成，但其致病基因中的三核苷酸為CTG，且位於非轉譯區，而非像其他型SCAs絕大多數為轉譯區中的CAG擴增。此外，SCA8基因所轉錄RNA的5端，與KLHL1基因之mRNA的5端互補，即為KLHL1基因的反意RNA。本論文的第二部份為利用細胞與基因轉殖小鼠模式來探討SCA8的可能致病機轉。在細胞模式中，我們發現CTG擴增的SCA8對於KLHL1基因表現的抑制較不若正常SCA8來得強；此外，雖然之前的研究認為SCA8基因並不會進行轉譯，但我們的研究證實了SCA8基因中的開放解讀架構（open reading frame，ORF）確實可以轉譯成蛋白質，且CTG擴增的SCA8與ORF1都會形成細胞內不可溶的包涵體。因此，SCA8的反意調控與可轉譯的開放解讀架構都可能與致病過程相關。我們亦建立SCA8的基因轉殖小鼠模式，雖然行為測定與小腦組織形態上都未發現異狀，但卻出現四肢緊抱（clasping）的現象。因此，此現象或許可提供作為致病機轉或是藥物研究之指標。

Spinocerebellar ataxias (SCAs) comprise a heterogeneous neurodegenerative disorders that are dominantly inherited. Among the identified SCAs, the trinucleotide or pentanucausing mutations have been shown to cause most SCAs. However, the prevalence of SCAs varies among populations. In the first part, in order to set up a database of the trinucleotide- and pentanucleotide-repeat expansions leading to SCA, we have assessed the repeat size at the SCA1, SCA2, MJD/SCA3, SCA6, SCA8, SCA10, SCA12, SCA17, and DRPLA loci. MJD/SCA3 (46%) was the most common autosomal dominant SCA in the Taiwanese cohort, followed by SCA6 (18%) and SCA1 (3%). The frequencies of large normal alleles are closely associated with the prevalence of SCA1, SCA2, MJD/SCA3, SCA6, and DRPLA among Taiwanese, Japanese, and Caucasians. In addition, abnormal expansion of SCA8 and SAC17 genes were detected in patients with PD, suggesting these two mutations might manifest as non-cerebellar symptoms.
Unlike most SCAs caused by expansion of a coding CAG trinucleotide repeat, SCA8 has been shown to link to CTG triplet repeat expansion in the 3' untranslated region of SCA8 gene on 13q21. The 5' end of the SCA8 transcript overlaps the transcription and translation start sites, as well as the first splice donor sequence of the Kelch-like 1 (KLHL1) gene of the complementary strand. The aim of the other part is to uncover the plausible mechanisms using cell and transgenic mouse as model systems. In vitro studies demonstrated that the suppressive activity for KLHL1 was significantly different between SCA8 transcripts carrying 0 and 157 combined repeats, and that SCA8 RNA was translatable. Both the expressed GFP-tagged ORF1 and polyleucine-expansion ORF3 proteins formed aggregates. Thus, SCA8 trans effects and polyleucine-containing aggregateds might be correlated with the pathogenesis of SCA8. In addition, the SCA8 overexpression transgenic mouse model showed no difference of motor activity and histopathological morphology of Purkinje cells between transgenic mice and their control littermates. However, hind-limb clasping was observed in transgenic mice with 157 repeats during tail suspension. Although no marked pathological phenotypes were found in our model, the clasping phenotype might be used to be a characteristic evaluation index for drugs screening as in Huntington’s disease mice.

洪葦苓 (2005) 第八型脊髓小腦運動失調症:CTG三核苷重複的遺傳分析與細胞模式研究。國立臺灣師範大學生命科學系碩士論文
項聖文 (2005) 第八型脊髓小腦運動失調症之果蠅模式建立與致病機制研究。國立臺灣師範大學生命科學系碩士論文
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