首页> 外文OA文献 >The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alpha B-crystallin and HSP27
【2h】

The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alpha B-crystallin and HSP27

机译:导致亚历山大疾病的神经胶质纤维酸性蛋白突变体R416W通过涉及细丝聚集以及αB-晶状体蛋白和HSP27缔合的途径积累到罗森塔尔纤维中

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务,本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文,但由于OA文献来源多样且变更频繁,仍可能出现获取不到、文献不完整或与标题不符等情况,如果获取不到我们将提供退款服务。请知悉。

摘要

[[abstract]]Here, we describe the early events in the disease pathogenesis of Alexander disease. This is a rare and usually fatal neurodegenerative disorder whose pathological hallmark is the abundance of protein aggregates in astrocytes. These aggregates, termed "Rosenthal fibers," contain the protein chaperones alpha B-crystallin and HSP27 as well as glial fibrillary acidic protein (GFAP), an intermediate filament (IF) protein found almost exclusively in astrocytes. Heterozygous, missense GFAP mutations that usually arise spontaneously during spermatogenesis have recently been found in the majority of patients with Alexander disease. In this study, we show that one of the more frequently observed mutations, R416W, significantly perturbs in vitro filament assembly. The filamentous structures formed resemble assembly intermediates but aggregate more strongly. Consistent with the heterozygosity of the mutation, this effect is dominant over wild-type GFAP in coassembly experiments. Transient transfection studies demonstrate that R416W GFAP induces the formation of GFAP containing cytoplasmic aggregates in a wide range of different cell types, including astrocytes. The aggregates have several important features in common with Rosenthal fibers, including the association of alpha B-crystallin and HSP27. This association occurs simultaneously with the formation of protein aggregates containing R416W GFAP and is also specific, since HSP70 does not partition with them. Monoclonal antibodies specific for R416W GFAP reveal, for the first time for any IF-based disease, the presence of the mutant protein in the characteristic histopathological feature of the disease, namely Rosenthal fibers. Collectively, these data confirm that the effects of the R416W GFAP are dominant, changing the assembly process in a way that encourages aberrant filament-filament interactions that then lead to protein aggregation and chaperone sequestration as early events in Alexander disease.
机译:[[摘要]]在此,我们描述亚历山大疾病的发病机理中的早期事件。这是一种罕见且通常致命的神经退行性疾病,其病理标志是星形胶质细胞中大量蛋白质聚集。这些聚集体称为“ Rosenthal纤维”,包含蛋白伴侣αB-晶状蛋白和HSP27以及神经胶质纤维酸性蛋白(GFAP),这是一种几乎仅在星形胶质细胞中发现的中间丝(IF)蛋白。最近在大多数亚历山大疾病患者中发现了杂合,错义的GFAP突变,通常在精子发生过程中自发地发生。在这项研究中,我们表明,最常观察到的突变之一R416W显着干扰了体外丝的组装。形成的丝状结构类似于组装中间体,但聚集更牢固。与突变的杂合性一致,在协同装配实验中,这种效应比野生型GFAP显着。瞬时转染研究表明,R416W GFAP可在包括星形胶质细胞在内的多种不同细胞类型中诱导含有GFAP的细胞质聚集体的形成。聚集体具有与Rosenthal纤维相同的几个重要特征,包括αB-晶状体蛋白和HSP27的缔合。这种结合与包含R416W GFAP的蛋白质聚集体的形成同时发生,并且也是特异性的,因为HSP70不与它们分隔。对任何基于IF的疾病,R416W GFAP特异的单克隆抗体首次揭示该疾病的特征性组织病理学特征即Rosenthal纤维中存在突变蛋白。总而言之,这些数据证实了R416W GFAP的作用占主导地位,从而改变了组装过程,从而鼓励了异常的细丝-细丝相互作用,继而导致蛋白质聚集和分子伴侣螯合成为亚历山大病的早期事件。

著录项

  • 作者

    Perng MD;

  • 作者单位
  • 年度 2010
  • 总页数
  • 原文格式 PDF
  • 正文语种 [[iso]]en
  • 中图分类

相似文献

  • 外文文献
代理获取

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号