Genome-wide screen for modifiers of ataxin-3 neurodegeneration in drosophila
Genome-wide screen for modifiers of ataxin-3 neurodegeneration in drosophila
复制标题
DOI：
10.1371/journal.pgen.003177
复制
发表时间：
2007-10-01
期刊：
影响因子：
4.5
通讯作者：
Bonini, Nancy M.
中科院分区：
文献类型：
--
作者：
Bilen, Julide;Bonini, Nancy M.
脊髓小脑型共济失调-3(SCA3)是最常见的显性遗传性共济失调之一，是由编码谷氨酰胺的CAG重复序列在基因内扩增引起的九种毁灭性的人类神经退行性疾病之一。多聚谷氨酰胺结构域对Aaxin-3蛋白具有毒性，导致神经元功能障碍和丢失。虽然已经确定了多谷氨酰胺毒性的修饰物，但关于修饰物如何作用于毒性的机制知之甚少。为了揭示脊髓小脑型共济失调3型，我们对由Aaxin-3诱导的致病性神经变性的果蝇进行了遗传筛查，并确定了25个修饰物，定义了18个基因。尽管预测了多种分子活性，但生物学分析表明，修饰剂影响了蛋白质的错误折叠。详细的机制研究表明，一些修饰物通过依赖蛋白酶体的方式影响蛋白质的积累，而另一些修饰物则影响自噬。Aaxin-3的部分修饰物也影响tau，揭示了由于不同的人类神经毒性蛋白导致的退行性变之间的共同途径。这些发现为多聚Q毒性的分子途径提供了新的见解，为促进人类神经退行性疾病的神经元存活定义了新的靶点。
Spinocerebellar ataxia type-3 (SCA3) is among the most common dominantly inherited ataxias, and is one of nine devastating human neurodegenerative diseases caused by the expansion of a CAG repeat encoding glutamine within the gene. The polyglutamine domain confers toxicity on the protein Ataxin-3 leading to neuronal dysfunction and loss. Although modifiers of polyglutamine toxicity have been identified, little is known concerning how the modifiers function mechanistically to affect toxicity. To reveal insight into spinocerebellar ataxia type-3, we performed a genetic screen in Drosophila with pathogenic Ataxin-3-induced neurodegeneration and identified 25 modifiers defining 18 genes. Despite a variety of predicted molecular activities, biological analysis indicated that the modifiers affected protein misfolding. Detailed mechanistic studies revealed that some modifiers affected protein accumulation in a manner dependent on the proteasome, whereas others affected autophagy. Select modifiers of Ataxin-3 also affected tau, revealing common pathways between degeneration due to distinct human neurotoxic proteins. These findings provide new insight into molecular pathways of polyQ toxicity, defining novel targets for promoting neuronal survival in human neurodegenerative disease.