B07 Aggregation-prone Proteins Exacerbate Huntingtin Toxicity In Yeast And Drosophila
B07 Aggregation-prone Proteins Exacerbate Huntingtin Toxicity In Yeast And Drosophila
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B07 易聚集蛋白会加剧酵母和果蝇中亨廷顿蛋白的毒性
DOI：
10.1136/jnnp-2014-309032.35
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Branco Dos Santos J
中科院分区：
文献类型：
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作者：
Branco Dos Santos J
背景突变型亨廷顿蛋白（HTT）的错误折叠和聚集是亨廷顿病（HD）发病机制的基础。在酵母中，一套易于聚集的蛋白质调节突变HTT毒性和聚集。特别是，酵母Rnq 1朊病毒蛋白（[PIN+]）是需要突变HTT毒性和聚集在这种生物体中，这表明朊病毒样蛋白在HD发病机制中的可能作用。了解朊蛋白介导的突变型HTT毒性的机制可能为进一步了解这种破坏性疾病的分子基础提供帮助。目的我们的目标是阐明聚集倾向蛋白对HTT聚集和毒性的影响。我们利用面包酵母酿酒酵母和果蝇来验证RNQ 1和突变HTTin的过表达的效果结果/结果RNQ 1的过表达-不依赖于突变体HTT表达-导致细胞毒性，如通过点样测定中酵母生长减少所证明的。编码犬尿氨酸3-单加氧酶（KMO）的酵母基因BNA 4（HD中的候选药物靶标）的遗传缺失改善了RNQ 1和突变HTT毒性。在GAL 4/UAS系统控制下表达RNQ 1的果蝇表现出神经元损失的显著增加和寿命的减少。此外，发生在酵母中，我们发现RNQ 1过表达增强突变HTT毒性在Drosophila.ConclusionsThese初步研究表明，聚集倾向的蛋白质可以是相关的HD发病机制。此外，这项工作进一步支持KMO作为HD和其他涉及蛋白质错误折叠和聚集的人类病理学的有前途的治疗靶点。
BackgroundThe misfolding and aggregation of mutant huntingtin (HTT) underlies the pathogenesis of Huntington’s disease (HD). In yeast, a suite of aggregation-prone proteins modulates mutant HTT toxicity and aggregation. In particular, the yeast Rnq1 prion protein ([PIN+]) is required for mutant HTT toxicity and aggregation in this organism, suggesting a possible role for prion-like proteins in HD pathogenesis. Understanding the mechanisms involved in the toxicity of mutant HTT mediated by prion proteins may provide further insight into the molecular basis of this devastating disorder.AimsOur goal was to elucidate the effects of aggregation-prone proteins upon HTT aggregation and toxicity.Methods/techniquesWe employed the baker’s yeast Saccharomyces cerevisiae and the fruit fly Drosophila melanogaster to characterise the effect of the overexpression of RNQ1 and mutant HTTin vivo.Results/outcomeOverexpression of RNQ1 – independent of mutant HTT expression – led to cellular toxicity as evidenced by reduced yeast growth in spotting assays. Genetic deletion of the yeast gene BNA4 – which encodes kynurenine 3-monooxygenase (KMO), a candidate drug target in HD – ameliorated both RNQ1 and mutant HTT toxicity. Drosophila expressing RNQ1 under the control of the GAL4/UAS system showed a significant increase in neuronal loss and a decrease in lifespan. Furthermore, as occurs in yeast, we found that RNQ1 overexpression potentiates mutant HTT toxicity in Drosophila.ConclusionsThese initial studies suggest that aggregation-prone proteins can be relevant for HD pathogenesis. Furthermore, this work further supports KMO as a promising therapeutic target for HD and other human pathologies involving protein misfolding and aggregation.