Identification of novel genes that modify phenotypes induced by Alzheimer's β-amyloid overexpression in Drosophila
Identification of novel genes that modify phenotypes induced by Alzheimer's β-amyloid overexpression in Drosophila
复制标题
DOI：
10.1534/genetics.107.078394
复制
发表时间：
2008-03-01
期刊：
影响因子：
3.3
通讯作者：
Konsolaki, Mary
中科院分区：
文献类型：
--
作者：
Cao, Weihuan;Song, Ho-Juhn;Konsolaki, Mary
预期寿命的持续增长强调了管理晚年高发病率疾病的重要性，例如各种神经退行性疾病。阿尔茨海默病（Alzheimer's disease，AD）是其中最常见的一种疾病，因此人们对其进行了大量的研究。虽然人们对AD的病理学和β-淀粉样蛋白（A β）肽的作用已经有了很多了解，但我们仍然不清楚A β代谢和毒性的完整相互作用网络。为了解决这一问题，我们使用表达A β的转基因果蝇进行了遗传相互作用筛选，并确定了影响A β代谢和毒性的突变。这些分析强调了各种生化过程的参与，如分泌，胆固醇稳态，染色质结构和功能的调节等，介导毒性A β效应。我们发现的几个突变以前没有与A β毒性相关，因此构成了AD干预的新的潜在靶点。我们还测试了这些突变与tau蛋白和扩展多聚谷氨酰胺过表达的相互作用，并发现了一些可能介导神经退行性变常见机制的候选突变。我们的数据提供了深入了解A β的毒性，并为进一步研究AD发病机制开辟了新的领域。
Sustained increases in life expectancy have underscored the importance of managing diseases with a high incidence in late life, such as various neurodegenerative conditions. Alzheimer's disease (AD) is the most common among these, and consequently significant research effort is spent on studying it. Although a lot is known about the pathology of AD and the role of beta-amyloid (A beta) peptides, the complete network of interactions regulating A beta metabolism and toxicity still eludes us. To address this, we have conducted genetic interaction screens using transgenic Drosophila expressing A beta and we have identified mutations that affect A beta metabolism and toxicity. These analyses highlight the involvement of various biochemical processes such as secretion, cholesterol homeostasis, and regulation of chromatin structure and function, among others, in mediating toxic A beta effects. Several of the mutations that we identified have not been linked to A beta toxicity before and thus constitute novel potential targets for AD intervention. We additionally tested these mutations for interactions with tau and expanded-polyglutamine overexpression and found a few candidate mutations that may mediate common mechanisms of neurodegeneration. Our data offer insight into the toxicity of A beta and open new areas for further study into AD pathogenesis.