Wang Dongdong, Sun Zhixin, Wen Pei, Zhao Mengyang, He Yuheng, Gou Fengting, Wang Jingjing, Fan Qing, Li Xueyuan, Ma Tianying, Wang Xiaoyu, Li Wen, Chen Sen, Zhao Deming, Yang Lifeng
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Animal Model Exp Med. 2025 Aug;8(8):1347-1363. doi: 10.1002/ame2.70048. Epub 2025 Jul 9.
Prion diseases (PrDs) are fatal transmissible neurodegenerative disorders caused by misfolded prion protein, which is highly expressed in the brain. Drosophila has been employed as a model system for studying mammalian neurodegenerative diseases.
Drosophila transgenic for hamster prion protein (HaPrP) was generated by Valium20 transformation. Locomotion, longevity, protease resistance, and histology were assessed, and nontargeted metabolomics analyses were performed to investigate the changes in Drosophila metabolism with the HaPrP expression and metformin treatment.
The Drosophila model exhibited pan-neuronal expression of HaPrP, with expression levels increasing with age. Flies displayed reduced climbing ability, shortened lifespan, and vacuolar structures in the brain. Additionally, HaPrP expressed in older flies demonstrated resistance to digestion by 5 μg/mL Proteinase K. The Drosophila model also displayed alterations in protein, lipid, and carbohydrate metabolism. We hypothesize that glutamate, N-acetylaspartate, ceramide, phosphatidylethanolamine, dihydroxyacetone phosphate, ribose-5-phosphate, and pyruvate are key metabolites potentially related to PrDs. Metformin improved locomotor activity, reduced PrP formation, and ameliorated mitochondrial dysfunction in flies, which may be associated with alterations in succinate, pyruvate, choline, and sphingomyelin levels.
We generated a Drosophila model of PrDs that recapitulates key pathological features observed in mammals. Preliminary applications have demonstrated that the Drosophila model is suitable for PrDs research and the high-throughput screening of potential therapeutic compounds.
朊病毒病（PrDs）是由错误折叠的朊病毒蛋白引起的致命性可传播神经退行性疾病，该蛋白在大脑中高度表达。果蝇已被用作研究哺乳动物神经退行性疾病的模型系统。
通过Valium20转化法构建了表达仓鼠朊病毒蛋白（HaPrP）的转基因果蝇。评估了果蝇的运动能力、寿命、蛋白酶抗性和组织学，并进行了非靶向代谢组学分析，以研究HaPrP表达和二甲双胍处理对果蝇代谢的影响。
果蝇模型表现出HaPrP的全神经元表达，表达水平随年龄增加。果蝇表现出攀爬能力下降、寿命缩短和大脑中的空泡结构。此外，老年果蝇中表达的HaPrP对5μg/mL蛋白酶K的消化具有抗性。果蝇模型还显示出蛋白质、脂质和碳水化合物代谢的改变。我们推测谷氨酸、N-乙酰天冬氨酸、神经酰胺、磷脂酰乙醇胺、磷酸二羟丙酮、5-磷酸核糖和丙酮酸是可能与朊病毒病相关的关键代谢物。二甲双胍改善了果蝇的运动活性，减少了PrP的形成，并改善了线粒体功能障碍，这可能与琥珀酸、丙酮酸、胆碱和鞘磷脂水平的改变有关。
我们构建了一个朊病毒病的果蝇模型，该模型概括了在哺乳动物中观察到的关键病理特征。初步应用表明，果蝇模型适用于朊病毒病研究和潜在治疗化合物的高通量筛选。
