In a screen for stress resistant fly mutants, we have identified a mutant fly EP2456 exhibited a down-regulation of rpi, lifespan extension, and oxidative stress resistance. The knockdown of rpi in the fly eyes and nervous system can extend lifespan but relative increasing in ubiquitous expression. Since oxidative damage is one of the major causes in many progressive neurodegenerative diseases such as Huntington’s disease, we examine whether the knockdown of rpi could modulate polyglutamine (polyQ) toxicity in the fly eye. The expression of polyQ in the fly eyes by GMR-Gal4 displays a rough eye phenotype without eye color. The knockdown of rpi in the polyQ expression fly eyes rescue the eye color back to red like wild type. However, it has little effect on distribution and aggregation of polyQ inclusions in the affected neurons. We found the down-regulation of rpi improves internal retinal structure and reduce cell death caused by polyQ toxicity. The toxicity of the adult-onset polyQ expression under Rh1-Gal4 driver was attenuated upon the knockdown of rpi. Several known factors in the suppression of polyQ toxicity like CBP, HSP40, HSP70, SOD1, P53, and XDH were checked their expression levels under the knockdown of rpi. However, the underlying mechanism by which the knockdown of rpi modulates polyQ toxicity seems not to be involved. In summary, down-regulation of rpi in the fly had beneficial effects on longevity, resistance to oxidative stress and alleviates polyQ toxicity.
利用篩選抗多重壓力突變株果蠅時,我們發現有一株突變的果蠅EP2456,其ribose-5-phosphate isomerase (rpi) 表現量降低,同時具有長壽以及較好的抗氧化壓力的特性。我們降低rpi的表現量在果蠅的眼睛以及神經系統裡有長壽的特性。然而,rpi表現量的增加並不會使其壽命以及抗氧化壓力變差。氧化的傷害為造成神經退化疾病的原因之一,例如亨丁頓舞蹈症(Huntington's Disease),所以我們想了解rpi表現量的降低是否可以調節在果蠅眼睛中表現長鍊麩醯胺酸(polyglutamine,polyQ)之毒性。我們利用GMR-Gal4將polyQ表現在果蠅的眼睛所呈現的特徵為粗糙並無顏色的眼睛。當我們在此遺傳背景去降低rpi的表現量可以將果蠅的眼睛變得像正常果蠅眼睛一樣。然而,rpi表現量的降低對於在神經細胞由polyQ所形成的包含體(inclusion)之分佈和聚集並沒有顯著的影響。此外,我們也發現rpi表現量的降低可以增進視網膜內層的結構以及減少polyQ毒性所引起的細胞死亡。利用Rh1-Gal4即在成蟲開始表現polyQ時,rpi表現量降低也可以減緩polyQ之毒性。一些已知可以調節polyQ的因子,例如:CBP, HSP40, HSP70, SOD1, P53, 以及眼睛色素合成酵素XDH,已被實驗檢測知道與之無關。總之,rpi表現量的降低不僅可以增長壽命,增加抗氧化壓力,還可以調節由polyQ所造成的毒性。
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