Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease
Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease
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DOI：
10.1172/jci57552
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发表时间：
2011-11-01
影响因子：
15.9
通讯作者：
Saudou, Frederic
中科院分区：
文献类型：
--
作者：
Keryer, Guy;Pineda, Jose R.;Saudou, Frederic
亨廷顿病（Huntington disease，HD）是一种破坏性常染色体显性遗传的神经退行性疾病。它是由亨廷顿蛋白（HTT）基因第一个外显子中CAG重复序列的扩增引起的，HTT基因编码一种在氨基末端具有多聚谷氨酰胺（polyQ）扩增的突变HIT蛋白。在这里，我们表明，野生型HTT通过亨廷顿相关蛋白1（HAP 1）与pericentriolar材料1蛋白（PCM 1）的相互作用来调节纤毛发生。小鼠细胞中Htt的丧失损害了PCM1的逆行运输，从而减少了初级纤毛的形成。在小鼠中，室管膜细胞中Htt的缺失导致PCM 1错误定位、纤毛层改变和脑积水。致病性polyQ扩增导致小鼠纹状体细胞中PCM1的中心体积累和异常长的初级纤毛。在HD小鼠模型和HD患者中，室管膜细胞中的PCM 1蓄积与纤毛较长和纤毛层紊乱相关。较长的纤毛导致脑脊液流动的改变。因此，我们的数据表明，WT HIT是必不可少的蛋白质运输到中心体和正常的纤毛发生。在HD中，超形态纤毛发生可能影响信号传导和成神经细胞迁移，从而使脑内稳态失调并加剧疾病进展。
Huntington disease (HD) is a devastating autosomal-dominant neurodegeneradve disorder. It is caused by expansion of a CAG repeat in the first exon of the huntingtin (HTT) gene that encodes a mutant HIT protein with a polyglutamine (polyQ) expansion at the amino terminus. Here, we demonstrate that WT HTT regulates ciliogenesis by interacting through huntingtin-associated protein 1 (HAP1) with pericentriolar material 1 protein (PCM1). Loss of Htt in mouse cells impaired the retrograde trafficking of PCM1 and thereby reduced primary cilia formation. In mice, deletion of Htt in ependymal cells led to PCM1 mislocalizadon, alteration of the cilia layer, and hydrocephalus. Pathogenic polyQ expansion led to centrosomal accumulation of PCM1 and abnormally long primary cilia in mouse striatal cells. PCM1 accumulation in ependymal cells was associated with longer cilia and disorganized cilia layers in a mouse model of HD and in HD patients. Longer cilia resulted in alteration of the cerebrospinal fluid flow. Thus, our data indicate that WT HIT is essential for protein trafficking to the centrosome and normal ciliogenesis. In HD, hypermorphic ciliogenesis may affect signaling and neuroblast migration so as to dysregulate brain homeostasis and exacerbate disease progression.