Identification of anti-prion compounds as efficient inhibitors of polyglutamine protein aggregation in a zebrafish model
Identification of anti-prion compounds as efficient inhibitors of polyglutamine protein aggregation in a zebrafish model
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DOI：
10.1074/jbc.m607865200
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发表时间：
2007-03-23
影响因子：
4.8
通讯作者：
Schmid, Bettina
中科院分区：
文献类型：
--
作者：
Schiffer, Niclas W.;Broadley, Sarah A.;Schmid, Bettina
几种神经退行性疾病，包括亨廷顿病（HD），与多聚谷氨酰胺（polyQ扩展蛋白）的异常折叠和聚集有关。在这里，我们建立了斑马鱼，Danio rerio，作为脊椎动物HD模型，允许筛选polyQ聚集和毒性的化学抑制剂。在斑马鱼胚胎中表达后，亨廷顿蛋白（htt）的polyQ扩增片段在大的SDS不溶性包涵体中积累，再现了HD病理学的关键特征。对活斑马鱼中包涵体形成的真实的实时监测表明，包涵体通过快速掺入可溶性htt物质而生长。突变体htt的表达增加了胚胎形态异常的频率和凋亡的发生。引人注目的是，凋亡细胞在很大程度上没有可见的聚集体，这表明可溶性寡聚前体可能是毒性的原因。在非脊椎动物polyQ疾病模型中，分子伴侣Hsp 40和Hsp 70抑制polyQ聚集和毒性。使用新建立的斑马鱼模型，针对哺乳动物朊病毒的N '-亚苄基-苯甲酰肼类的两种化合物被证明是polyQ聚集的有效抑制剂，与朊病毒和polyQ疾病蛋白的聚集的共同结构机制一致。
Several neurodegenerative diseases, including Huntington disease (HD), are associated with aberrant folding and aggregation of polyglutamine (polyQ expansion proteins. Here we established the zebrafish, Danio rerio, as a vertebrate HD model permitting the screening for chemical suppressors of polyQ aggregation and toxicity. Upon expression in zebrafish embryos, polyQ-expanded fragments of huntingtin (htt) accumulated in large SDS-insoluble inclusions, reproducing a key feature of HD pathology. Real time monitoring of inclusion formation in the living zebrafish indicated that inclusions grow by rapid incorporation of soluble htt species. Expression of mutant htt increased the frequency of embryos with abnormal morphology and the occurrence of apoptosis. Strikingly, apoptotic cells were largely devoid of visible aggregates, suggesting that soluble oligomeric precursors may instead be responsible for toxicity. As in nonvertebrate polyQ disease models, the molecular chaperones, Hsp40 and Hsp70, suppressed both polyQ aggregation and toxicity. Using the newly established zebrafish model, two compounds of the N'-benzylidene-benzohydrazide class directed against mammalian prion proved to be potent inhibitors of polyQ aggregation, consistent with a common structural mechanism of aggregation for prion and polyQ disease proteins.