The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin:: Neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis
The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin:: Neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis
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DOI：
10.1073/pnas.041566798
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发表时间：
2001-02-13
影响因子：
11.1
通讯作者：
Néri, C
中科院分区：
文献类型：
--
作者：
Holbert, S;Denghien, I;Néri, C
亨廷顿病（HD）是由亨廷顿蛋白（htt）中的多聚谷氨酰胺扩增引起的神经退行性疾病。HD的发病机制似乎涉及形成泛素化的神经元核内包涵体，其含有N-末端突变的htt、异常的蛋白质相互作用以及多种蛋白质（明显地，转录因子）的聚集体隔离。为了在一个简单的模型系统中识别新的ht相互作用蛋白，我们使用了酵母双杂交筛选秀丽隐杆线虫激活结构域库。我们发现了一个预测的WW结构域蛋白（ZK1127.9），在双杂交测试中与htt的N-末端片段相互作用。ZK1127.9的人类同源物是CA 150，一种N-末端插入的转录共激活因子，含有由多态性重复DNA编码的不完全（Gln-Ala）（38）道。CA 150在体外与来自淋巴母细胞的全长htt相互作用。CA 150的表达，化学测量，显着增加，在人类HD脑组织与正常年龄匹配的人脑组织相比，和CA 150显示聚集体形成与部分共定位的泛素阳性聚集体。在432例HD患者中，CA 150重复序列长度解释了发病年龄的少量但具有统计学意义的变异性。我们的数据表明，CA 150的异常表达，介导的相互作用与聚谷氨酰胺扩大的htt，可能会改变转录，并在HD发病机制的作用。
Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine expansion in the protein huntingtin (htt). Pathogenesis in HD appears to involve the formation of ubiquitinated neuronal intranuclear inclusions containing N-terminal mutated htt, abnormal protein interactions, and the aggregate sequestration of a variety of proteins (noticeably, transcription factors). To identify novel htt-interacting proteins in a simple model system, we used a yeast two-hybrid screen with a Caenorhabditis elegans activation domain library. We found a predicted WW domain protein (ZK1127.9) that interacts with N-terminal fragments of htt in two-hybrid tests. A human homologue of ZK1127.9 is CA150, a transcriptional coactivator with a N-terminal insertion that contains an imperfect (Gln-Ala)(38) tract encoded by a polymorphic repeat DNA. CA150 interacted in vitro with full-length htt from lymphoblastoid cells. The expression of CA150, measured immunohistochemically, was markedly increased in human HD brain tissue compared with normal age-matched human brain tissue, and CA150 showed aggregate formation with partial colocalization to ubiquitin-positive aggregates. In 432 HD patients, the CA150 repeat length explains a small, but statistically significant, amount of the variability in the onset age. Our data suggest that abnormal expression of CA150, mediated by interaction with polyglutamine-expanded htt, may alter transcription and have a role in HD pathogenesis.