Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila
Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila
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DOI：
10.1093/hmg/9.1.13
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发表时间：
2000-01-01
影响因子：
3.5
通讯作者：
Thompson, LM
中科院分区：
文献类型：
--
作者：
Marsh, JL;Walker, H;Thompson, LM
几种显性的迟发性神经退行性疾病（例如，亨廷顿病）是由特定蛋白质内的多聚谷氨酰胺（polyQ）重复扩增引起的。这些疾病的多样性，但重叠的病理可能是由于新的有害功能独特的每种蛋白质或一个共同的病理生理学介导的长polyQ链本身。通过工程改造果蝇表达不同的polyQ肽，我们发现单独扩展的polyQ链本质上具有细胞毒性，并导致神经元变性和早期成人死亡。我们进一步发现，这种内在毒性取决于细胞类型和polyQ长度，并且包含其他氨基酸可以改变和降低毒性。这是第一个体内证据表明，当从其疾病基因背景中去除polyQ时，会导致神经毒性。这些研究提供了一个基础，了解不同的临床表现方面的内在细胞毒性作用的polyQ肽被蛋白质的背景。将细胞毒性polyQ扩增工程化到Dishevelled（一种含有天然存在的polyQ束的果蝇蛋白质）中的平行实验强烈表明，毒性polyQ肽的作用可以被蛋白质环境中和。该动物模型提供了一种简单有效的方法来筛选减轻polyQ诱导的致死性的治疗剂，而不依赖于任何特定的疾病基因。通过定量几种转基因品系中的致死程度，我们已经鉴定了许多遗传修饰的菌株，其适合于最终测试改善polyQ肽的病理的化合物或基因。
Several dominant, late-onset neurodegenerative diseases (e.g, Huntington's disease) are caused by expansion of polyglutamine (polyQ) repeats within specific proteins. The diverse, yet overlapping, pathology of these diseases could be due to novel deleterious functions unique to each protein or to a common pathophysiology mediated by the long polyQ chains themselves. By engineering Drosophila to express different polyQ peptides, we find that expanded polyQ chains alone are intrinsically cytotoxic and cause neuronal degeneration and early adult death. We further find that this intrinsic toxicity is dependent on cell type and polyQ length and that the inclusion of other amino acids modifies and reduces toxicity. This is the first in vivo evidence that polyQs, when removed from their disease gene context, cause neurotoxicity. These studies provide a basis for understanding the diverse clinical presentations in terms of the intrinsic cytotoxic effect of polyQ peptides being modulated by protein context. parallel experiments in which cytotoxic polyQ expansions were engineered into Dishevelled, a Drosophila protein containing a naturally occurring polyQ tract, strongly suggest that the effect of a toxic polyQ peptide can be neutralized by protein context, This animal model provides a simple and effective means of screening for therapeutics that relieves the polyQ-induced lethality, independent of any particular disease gene. By quantifying the degree of lethality in several transgenic lines, we have identified a number of genetically modified strains that are suitable for eventual testing of compounds or genes that ameliorate the pathology of polyQ peptides.