亨丁頓舞蹈症是一種神經退化性疾病，與多麩醯胺酸鏈 (Polyglutamine)聚合的累積有關。目前尚未找到治療的方法。已有研究利用數種篩選平台篩選出改善多麩醯胺酸鏈聚合和毒性的基因。在我們先前的研究，已篩選出三株DGRC的果蠅可以緩解因多麩醯胺酸鏈毒性造成的粗糙眼。在這裡，我們發現DGRC202462、DGRC205154及DGRC205444這三株果蠅可減緩亨丁頓舞蹈症轉基因果蠅的HTT97Q毒性及蛋白質聚合。此外，DGRC205444果蠅株藉由elav-Gal4和appl-Gal4的驅動，可增強母果蠅氧化壓力耐受性。CG13025、CG8379 及CRMP基因表現量分別在DGRC202462、DGRC205154及DGRC205444這三株果蠅中有提高的現象。我們發現CG13025轉基因果蠅在elav-Gal4驅動下，只有母果蠅可以改善氧化壓力的耐受性。此外，CRMP 及CG8379基因具有部分緩解HTT毒性的能力。這個研究為亨丁頓舞蹈症提供了具有潛力的治療標靶。

Huntington’s disease is a neurodegenerative disease associated with accumulation of polyglutamine aggregations. There is no cure for this disease yet. Several screens to identify the genes to ameliorate polyglutamine aggregation and toxicity have been reported. In our previous screen, we identified that the three DGRC lines able to rescue the polyglutamine-induced rough eye in Drosophila. Here I discovered that the three DGRC202462, DGRC205154 and DGRC205444 fly lines have the ability to reduce HTT97Q toxicity and protein aggregations in HD transgenic flies. Moreover, the DGRC205444 fly line driven by elav-Gal4 and appl-Gal4 in female can enhance tolerance to oxidative stress. CG13025, CG8379 and CRMP are upregulated in DGRC202462, DGRC205154 and DGRC205444 fly lines, respectively. We found that CG13025 transgenic flies can improve the resistance to oxidative stress only in female by elav-Gal4. In addition, CRMP and CG8379 are able to partially relieve HTT toxicity. The study provides potential therapeutic targets for Huntington’s disease.

Abstract.........................................................................................................................I
中文摘要.......................................................................................................................II
致謝…….....................................................................................................................III
Contents .....................................................................................................................Ⅳ
Introduction .................................................................................................................1
Huntington’s disease ................................................................................................1
Drosophila melanogaster as genetic models for polyglutamine disease ................2
Noncoding RNAs and neurodegenerative diseases ................................................3
Materials and Methods ................................................................................................5
Fly strains and culture conditions ...........................................................................5
Fly Eye Imaging and Fluorescence Imaging in Neuro-2a Cells ............................5
Cell Culture and Transfection..................................................................................5
Filter-trap assay and slot blot assay.........................................................................6
RNA preparation and semi-quantitative RT-PCR ................................................7
Quantitative real-time PCR (Q-PCR) ....................................................................8
Plasmid construction ...............................................................................................8
Oxidative stress test..................................................................................................9
Results .........................................................................................................................10
The three of Drosophila lines DGRC202462, DGRC205154, and DGRC205444 can reduce the polyglutamine toxicity and partially relieve the apoptosis in transgenic flies.........................................................................................................10
The DGRC205444 fly line expressing in nervous system can enhance tolerance to oxidative stress…………………………………………………………………11
The three Drosophila lines DGRC202462, DGRC205154, and DGRC205444 can reduce toxicity and protein aggregations of HTT in HD transgenic flies...........................................................................................................................12
CRMP is upregulated in DGRC205444 fly line and partially relieve HTT toxicity in HD transgenic flies……………………………………………………………..13
CG13025 is upregulated in DGRC202462 fly line but cannot improve tolerance to oxidative stress neither rescue the rough eyes by Htt97Q………………........14
CG8379 is upregulated in DGRC205154 fly line and partially relieve HTT toxicity in HD transgenic flies……………………………………………………15
Both the gene CG8379 and CG13025 in Drosophila melanogaster cannot reduce protein aggregations of HTT in Neuro-2a cell.......................................................16
Discussion....................................................................................................................17
Figures.........................................................................................................................21
Appendix.....................................................................................................................40
Tables...........................................................................................................................43
References...................................................................................................................50

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