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

Generation and Pathogenic Study of SCA8 Drosophila Model

項聖文(Sheng-Weng Hsiang)

指導教授 ： 蘇銘燦

國立臺灣師範大學/理學院/生命科學研究所/碩士(2004年)

摘要

無資料

關鍵字

脊髓小腦運動失調症 ； 聚白胺基酸蛋白 ； 熱休克蛋白 ； 核酸結合蛋白 ； 神經退化疾病 ； HASH(0x9778b80) ； HASH(0x9778bf8) ； HASH(0x9778c70) ； HASH(0x977994c)

並列摘要

Abstract
The spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders characterized by cerebellar dysfunction alone or in combination with other neurological abnormalities. SCA type 8 (SCA8) has been attributed to the expanded CTG repeat at 3’ end of SCA8 gene on chromosome 13q21. To unravel the pathogenic mechanisms underlying SCA8 we tried to establish SCA8 Drosophila models in this study. The photoreceptor cells were degenerated when SCA8 gene with expanded CTG repeats were expressed in the transgenic flies, suggesting the repeat sequence exhibits pathogenic effect. The repeat containing transcripts were found accumulated in nuclei as RNA foci using in situ hybridization. As sequence analysis of SCA8 gene did not reveal that SCA8 encodes any significant ORFs in previous study, suggesting that SCA8 will not encode any protein product. Nevertheless, expression constructs with EGFP fused at 3’ end of SCA8 were able to express in the eye discs of transgenic flies, suggesting that SCA8 may contain translatable ORF. Expressing the repeat containing ORF in transgenic flies cause severe degenerative phenotype. However the transcripts were aggregated in RNA foci and can not be transported to cytosol to be translated into polyLeu containing polypeptide. From these results we have learned that SCA8 can exert its cytotoxcity effect at RNA level. Previous studies demonstrated that RNA binding proteins, such as muslcle-blind and PKAAP, were associated with CUG containing transcripts to form RNA foci, which sequesters the expression level of these RNA binding proteins and enhance the pathogenic effect. We found our SCA8 fly model displayed different degenerative phenotype when placed at mbl, and PKAAP mutant background. Interestingly, the chaperone protein, Hsp70, was found alleviated SCA8 disease presentation. It is very likely that mis-folded proteins may also play a role in SCA8 pathogenesis. Since 5’ end of SCA8 is overlapped with a nearby gene KLHL1, we would like to know whether KLHL1 is also play a role in SCA8 pathogenesis. Retinal expression of KLHL1 did not cause obviously eye degeneration. Co-expression of both SCA8 and KLHL1 did not enhance the disease phenotype. This has demonstrated that KLHL1 may not participate in the pathogenesis of SCA8.

並列關鍵字

SCA8 ； KLHL1 ； HSP70 ； PKAAP ； CTG ； IRES ； RNA foci ； ORF3 ； rough eye ； polyL

參考文獻

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