抑制調控果蠅5-磷酸核醣異構酶能減輕Tau引起的毒性

Down-regulation of ribose-5-phosphate isomerase attenuates Tau mediated toxicity in Drosophila

蕭欣杰(Hsin-Chieh Shiau)

指導教授 ： 蘇銘燦

國立臺灣師範大學/理學院/生命科學系/博士(2015年)

https://doi.org/10.6345/NTNU202205436

摘要

Tauopathy是一種多因子疾病，透過遺傳及分子方法已確認出許多致病途徑。為探究Tau引起的毒性及找出新的治療標的，我們利用眼睛及背毛模式去篩選與其他神經退化疾病有關的致病因子。在篩選研究中，靜默5-磷酸核醣異構酶(rpi)基因呈現出最佳的性狀改善結果。本研究指出在神經中抑制調控rpi基因表現可以延長tauopathy果蠅的壽命及改善運動功能。而在西方墨點實驗結果，顯示出tauopathy果蠅性狀改善不是經由改變Tau蛋白質的磷酸化。此外，進一步發現tauopathy果蠅細胞中煙草醯胺腺嘌呤二核苷酸磷酸鹽(NADPH)及還原態穀胱甘肽(GSH)濃度會上升。我們也得到過量表現TTLL1可減緩Tau的毒性及延長tauopathy果蠅的壽命。因此，在果蠅模式中，減少rpi的表現及大量表現TTLL1可以抑制Tau的毒性。

關鍵字

5-磷酸核醣異構酶

並列摘要

Tauopathy is a multifactorial disease in which many pathogenic pathways have been identified through genetics and molecular approaches. To better evaluate Tau induced toxicity and to find novel therapeutic targets, we screen components of pathogenic pathways that might implicated in various neurodegenerative diseases using both eye and notal bristle as model systems. We have chosen to study ribose-5-phosphate isomerase (rpi), because silencing of rpi exhibited the greatest phenotypic improvement among all other modifiers in our screening. Our data indicated that reduced neuronal expression of rpi extends the lifespan and improves the motor function of tauopathy flies. Results of immunoblotting experiments reveal that the phosphorylated Tau species were not significantly decreased when rpi were downregulated, suggesting that the beneficial effect of reduced rpi on tauopathy flies is not mediated through altering the phosphorylation of Tau. Additionally, reduced rpi increases cellular nicotinamide adenine dinucleotide phosphate (NADPH) and reduced form of glutathione (GSH) in tauopathy flies. We also found that overexpression of Tubulin tyrosine ligase-like 1 (TTLL1) attenuates Tau toxicity and extend the lifespan of tauopathy flies. Taken together our findings demonstrate that reduced rpi expression and TTLL1 overexpression suppress Tau toxicity in Drosophila.

並列關鍵字

ribose-5-phosphate isomerase

參考文獻

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