突变亨廷顿蛋白淀粉样蛋白的形成:阈值,进行性和正常聚谷氨酰胺蛋白的募集。

C C Huang, P W Faber, F Persichetti, V Mittal, J P Vonsattel, M E MacDonald, J F Gusella
{"title":"突变亨廷顿蛋白淀粉样蛋白的形成:阈值,进行性和正常聚谷氨酰胺蛋白的募集。","authors":"C C Huang,&nbsp;P W Faber,&nbsp;F Persichetti,&nbsp;V Mittal,&nbsp;J P Vonsattel,&nbsp;M E MacDonald,&nbsp;J F Gusella","doi":"10.1023/b:scam.0000007124.19463.e5","DOIUrl":null,"url":null,"abstract":"<p><p>Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat encoding a tract of consecutive glutamines near the amino terminus of huntingtin, a large protein of unknown function. It has been proposed that the expanded polyglutamine stretch confers a new property on huntingtin and thereby causes cell and region-specific neurodegeneration. Genotype-phenotype correlations predict that this novel property appears above a threshold length (approximately 38 glutamines), becomes progressively more evident with increasing polyglutamine length, is completely dominant over normal huntingtin and is not appreciably worsened by a double genetic dose in HD homozygotes. Recently, an amino terminal fragment of mutant huntingtin has been found to form self-initiated fibrillar aggregates in vitro. We have tested the capacity for aggregation to assess whether this property matches the criteria expected for a fundamental role in HD pathogenesis. We find that that in vitro aggregation displays a threshold and progressivity for polyglutamine length remarkably similar to the HD disease process. Moreover, the mutant huntingtin amino terminus is capable of recruiting into aggregates normal glutamine tract proteins, such as the amino terminal segments of both normal huntingtin and of TATA-binding protein (TBP). Our examination of in vivo aggregates from HD post-mortem brains indicates that they contain an amino terminal segment of huntingtin of between 179 and 595 residues. They also contain non-huntingtin protein, as evidenced by immunostaining for TBP. Interestingly, like the in vitro aggregates, aggregates from HD brain display Congo red staining with green birefringence characteristic of amyloid. Our data support the view that the expanded polyglutamine segment confers on huntingtin a new property that plays a determining role in HD pathogenesis and could be a target for treatment. Moreover, the new property might have its toxic consequences by interaction with one or more normal polyglutamine-containing proteins essential for the survival of target neurons.</p>","PeriodicalId":21884,"journal":{"name":"Somatic Cell and Molecular Genetics","volume":"24 4","pages":"217-33"},"PeriodicalIF":0.0000,"publicationDate":"1998-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1023/b:scam.0000007124.19463.e5","citationCount":"281","resultStr":"{\"title\":\"Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins.\",\"authors\":\"C C Huang,&nbsp;P W Faber,&nbsp;F Persichetti,&nbsp;V Mittal,&nbsp;J P Vonsattel,&nbsp;M E MacDonald,&nbsp;J F Gusella\",\"doi\":\"10.1023/b:scam.0000007124.19463.e5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat encoding a tract of consecutive glutamines near the amino terminus of huntingtin, a large protein of unknown function. It has been proposed that the expanded polyglutamine stretch confers a new property on huntingtin and thereby causes cell and region-specific neurodegeneration. Genotype-phenotype correlations predict that this novel property appears above a threshold length (approximately 38 glutamines), becomes progressively more evident with increasing polyglutamine length, is completely dominant over normal huntingtin and is not appreciably worsened by a double genetic dose in HD homozygotes. Recently, an amino terminal fragment of mutant huntingtin has been found to form self-initiated fibrillar aggregates in vitro. We have tested the capacity for aggregation to assess whether this property matches the criteria expected for a fundamental role in HD pathogenesis. We find that that in vitro aggregation displays a threshold and progressivity for polyglutamine length remarkably similar to the HD disease process. Moreover, the mutant huntingtin amino terminus is capable of recruiting into aggregates normal glutamine tract proteins, such as the amino terminal segments of both normal huntingtin and of TATA-binding protein (TBP). Our examination of in vivo aggregates from HD post-mortem brains indicates that they contain an amino terminal segment of huntingtin of between 179 and 595 residues. They also contain non-huntingtin protein, as evidenced by immunostaining for TBP. Interestingly, like the in vitro aggregates, aggregates from HD brain display Congo red staining with green birefringence characteristic of amyloid. Our data support the view that the expanded polyglutamine segment confers on huntingtin a new property that plays a determining role in HD pathogenesis and could be a target for treatment. Moreover, the new property might have its toxic consequences by interaction with one or more normal polyglutamine-containing proteins essential for the survival of target neurons.</p>\",\"PeriodicalId\":21884,\"journal\":{\"name\":\"Somatic Cell and Molecular Genetics\",\"volume\":\"24 4\",\"pages\":\"217-33\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"1998-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1023/b:scam.0000007124.19463.e5\",\"citationCount\":\"281\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Somatic Cell and Molecular Genetics\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1023/b:scam.0000007124.19463.e5\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Somatic Cell and Molecular Genetics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1023/b:scam.0000007124.19463.e5","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 281

摘要

亨廷顿氏病(HD)是由一个扩展的CAG三核苷酸重复序列引起的,该重复序列在亨廷顿蛋白(一种功能未知的大蛋白)的氨基末端附近编码一段连续的谷氨酰胺。有人提出,扩大的聚谷氨酰胺拉伸赋予亨廷顿蛋白一种新的性质,从而导致细胞和区域特异性神经变性。基因型-表型相关性预测,这种新特性出现在阈值长度(约38个谷氨酰胺)以上,随着多聚谷氨酰胺长度的增加而逐渐变得更加明显,完全优于正常的亨廷顿蛋白,并且在HD纯合子中不会因双倍遗传剂量而明显恶化。最近,发现突变的亨廷顿蛋白的氨基末端片段在体外形成自启动的纤维聚集体。我们已经测试了聚集能力,以评估这种特性是否符合HD发病机制中基本作用的预期标准。我们发现,在体外聚集体显示一个阈值和进展的多聚谷氨酰胺长度非常相似的HD疾病的过程。此外,突变的亨廷顿蛋白氨基端能够招募到正常谷氨酰胺束蛋白的聚集体中,例如正常亨廷顿蛋白和tata结合蛋白(TBP)的氨基端片段。我们对HD死后大脑的体内聚集物的检查表明,它们含有亨廷顿蛋白的氨基末端区段,在179到595个残基之间。它们还含有非亨廷顿蛋白,正如TBP免疫染色所证明的那样。有趣的是,与体外聚集体一样,HD脑聚集体显示淀粉样蛋白的绿色双折射刚果红染色。我们的数据支持这样一种观点,即扩大的聚谷氨酰胺片段赋予亨廷顿蛋白一种新的特性,这种特性在HD发病机制中起决定性作用,可能成为治疗的靶点。此外,这种新特性可能通过与一种或多种正常的含谷氨酰胺的蛋白质相互作用而产生毒性后果,这些蛋白质对目标神经元的存活至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat encoding a tract of consecutive glutamines near the amino terminus of huntingtin, a large protein of unknown function. It has been proposed that the expanded polyglutamine stretch confers a new property on huntingtin and thereby causes cell and region-specific neurodegeneration. Genotype-phenotype correlations predict that this novel property appears above a threshold length (approximately 38 glutamines), becomes progressively more evident with increasing polyglutamine length, is completely dominant over normal huntingtin and is not appreciably worsened by a double genetic dose in HD homozygotes. Recently, an amino terminal fragment of mutant huntingtin has been found to form self-initiated fibrillar aggregates in vitro. We have tested the capacity for aggregation to assess whether this property matches the criteria expected for a fundamental role in HD pathogenesis. We find that that in vitro aggregation displays a threshold and progressivity for polyglutamine length remarkably similar to the HD disease process. Moreover, the mutant huntingtin amino terminus is capable of recruiting into aggregates normal glutamine tract proteins, such as the amino terminal segments of both normal huntingtin and of TATA-binding protein (TBP). Our examination of in vivo aggregates from HD post-mortem brains indicates that they contain an amino terminal segment of huntingtin of between 179 and 595 residues. They also contain non-huntingtin protein, as evidenced by immunostaining for TBP. Interestingly, like the in vitro aggregates, aggregates from HD brain display Congo red staining with green birefringence characteristic of amyloid. Our data support the view that the expanded polyglutamine segment confers on huntingtin a new property that plays a determining role in HD pathogenesis and could be a target for treatment. Moreover, the new property might have its toxic consequences by interaction with one or more normal polyglutamine-containing proteins essential for the survival of target neurons.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信