Investigation of the mechanism by which huntingtin fragments are produced and their pathogenic relevance to Huntington's disease
研究亨廷顿片段的产生机制及其与亨廷顿病的致病相关性
基本信息
- 批准号:MR/L003627/1
- 负责人:
- 金额:$ 46.2万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2013
- 资助国家:英国
- 起止时间:2013 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Huntington's disease (HD) is a neurodegenerative disorder with an average age of onset of 40 years. Affected individuals lose their ability to control movement, develop an impaired mental capacity and psychiatric problems and lose weight. The disease progresses for 15-20 years until death. There are effective treatments for some psychiatric problems (e.g. depression) but there is no way to halt or slow the disease progression. HD is inherited and offspring of affected individuals have a 50% chance of developing the disease. The only difference between the huntingtin gene (HTT) in people who become affected and those who remain disease free is the increased length of the DNA sequence CAG close to its beginning. This results in an extra long tract of glutamines (a building block for proteins) in the huntingtin protein (HTT). The extra glutamines cause the HTT protein to interact with itself and other proteins in an aberrant fashion but the mechanism by which this causes HD remains poorly understood. Fragments of HTT have been detected in the brains of HD patients and HD mouse models and a considerable amount of research indicates that HTT fragments are more important for the disease process than the full-length protein. Most research into the origin of these fragments has focussed on identifying the relevant proteases (enzymes that cleave proteins), but despite this, the origin of most fragments remains unknown. We have recently found that the smallest HTT fragment is generated by altered processing of the HTT gene and not by protease digestion. Most genes are composed of exons (DNA sequences that code for the protein) that are separated by introns. As the gene is transcribed into messenger RNA (mRNA), the introns are removed by splicing prior to protein production. The HTT gene is comprised of 67 exons and we have discovered that when the HD mutation is present, exon 1 of HTT does not always splice to exon 2, producing a small novel mRNA that contains exon 1 and intron 1 sequences and terminates in a polyA tail, that marks the end mRNA. This is translated to produce a small exon 1 HTT protein that has been shown to be highly pathogenic in multiple model systems. These results are important because understanding how this HTT fragment is generated will allow us to devise strategies to prevent its formation and thereby determine the extent to which it contributes to the disease process. An understanding of the processing of the HTT gene and the production of HTT fragments is a basic requisite to unraveling the pathogenic process that causes HD. In this proposal we shall:1. Further investigate the mechanism by which the HD mutation (extra long CAG sequence) results in the incomplete splicing of exon 1 HTT to exon 2. We have identified a splicing factor (SRSF6) that recognizes CAG repeat sequences, is known to modulate the splicing of genes and we have shown that it binds to the beginning of the HTT gene. We shall investigate the mechanism by which SRSF6 influences HTT splicing and identify other splicing factors that may be involved.2. Over the past ten years, we have performed an extensive characterization of various mouse models of HD. We shall use a new technology (zinc finger nucleases) to manipulate the Htt gene in HD mice in order to prevent the exon 1 HTT protein from being generated via this mis-splicing mechanism. This will ultimately allow us to determine the extent to which the exon 1 HTT protein contributes to the HD disease process.3. We have identified a number of additional HTT fragments in the brains of the HD mice. With the exception of exon 1 HTT, the identity and origin of these fragments remains unknown. We shall use a combination of chemical modification and protein sequencing to identify the ends of as many of these other fragments as possible. This may reveal strategies by which the formation of specific fragments can be prevented and their contribution to pathogenesis determined.
亨廷顿病(HD)是一种神经退行性疾病,平均发病年龄为40岁。受影响的人失去控制运动的能力,发展出受损的心理能力和精神问题,并减轻体重。这种疾病会持续15-20年,直到死亡。对于一些精神问题(例如抑郁症)有有效的治疗方法,但没有办法阻止或减缓疾病的进展。HD是遗传性的,受影响个体的后代有50%的机会发展这种疾病。亨廷顿基因(HTT)在受影响的人和那些保持疾病自由的人之间的唯一区别是DNA序列CAG接近其开始的长度增加。这导致亨廷顿蛋白(HTT)中的谷氨酰胺(蛋白质的构建块)的超长束。额外的谷氨酰胺导致HTT蛋白以异常的方式与自身和其他蛋白质相互作用,但这导致HD的机制仍然知之甚少。已在HD患者和HD小鼠模型的脑中检测到HTT的片段,并且大量研究表明HTT片段对于疾病过程比全长蛋白更重要。大多数对这些片段起源的研究都集中在鉴定相关的蛋白酶(切割蛋白质的酶)上,但尽管如此,大多数片段的起源仍然未知。我们最近发现,最小的HTT片段是通过改变HTT基因的加工而不是通过蛋白酶消化产生的。大多数基因由外显子(编码蛋白质的DNA序列)组成,外显子被内含子分开。当基因被转录成信使RNA(mRNA)时,内含子在蛋白质产生之前通过剪接被去除。HTT基因由67个外显子组成,我们发现当HD突变存在时,HTT的外显子1并不总是剪接到外显子2,产生一个小的新mRNA,其包含外显子1和内含子1序列,并终止于polyA尾,其标记末端mRNA。这被翻译以产生小的外显子1 HTT蛋白,其已在多个模型系统中显示出高致病性。这些结果很重要,因为了解HTT片段是如何产生的将使我们能够制定策略来防止其形成,从而确定它对疾病过程的贡献程度。了解HTT基因的加工和HTT片段的产生是解开导致HD的致病过程的基本要求。在本建议中,我们将:1。进一步研究HD突变(超长CAG序列)导致外显子1 HTT与外显子2不完全剪接的机制。我们已经确定了一个剪接因子(SRSF 6),识别CAG重复序列,已知调节基因的剪接,我们已经表明,它结合到HTT基因的开始。我们将研究SRSF 6影响HTT剪接的机制,并确定可能涉及的其他剪接因素。2.在过去的十年中,我们对各种HD小鼠模型进行了广泛的表征。我们将使用一种新的技术(锌指核酸酶)来操纵HD小鼠的Htt基因,以防止外显子1 HTT蛋白通过这种错误剪接机制产生。这将最终使我们能够确定外显子1 HTT蛋白在HD疾病过程中的作用程度。我们已经在HD小鼠的大脑中鉴定了一些额外的HTT片段。除了外显子1 HTT,这些片段的身份和来源仍然未知。我们将使用化学修饰和蛋白质测序相结合的方法来鉴定尽可能多的其他片段的末端。这可能揭示的策略,通过这些策略可以防止特定片段的形成,并确定它们对发病机制的贡献。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A common gene expression signature in Huntington's disease patient brain regions.
- DOI:10.1186/s12920-014-0060-2
- 发表时间:2014-10-30
- 期刊:
- 影响因子:2.7
- 作者:Neueder A;Bates GP
- 通讯作者:Bates GP
Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice.
- DOI:10.1038/s41598-017-14290-3
- 发表时间:2017-10-27
- 期刊:
- 影响因子:4.6
- 作者:Bondulich MK;Jolinon N;Osborne GF;Smith EJ;Rattray I;Neueder A;Sathasivam K;Ahmed M;Ali N;Benjamin AC;Chang X;Dick JRT;Ellis M;Franklin SA;Goodwin D;Inuabasi L;Lazell H;Lehar A;Richard-Londt A;Rosinski J;Smith DL;Wood T;Tabrizi SJ;Brandner S;Greensmith L;Howland D;Munoz-Sanjuan I;Lee SJ;Bates GP
- 通讯作者:Bates GP
Dysfunction of the CNS-heart axis in mouse models of Huntington's disease.
- DOI:10.1371/journal.pgen.1004550
- 发表时间:2014-08
- 期刊:
- 影响因子:4.5
- 作者:Mielcarek M;Inuabasi L;Bondulich MK;Muller T;Osborne GF;Franklin SA;Smith DL;Neueder A;Rosinski J;Rattray I;Protti A;Bates GP
- 通讯作者:Bates GP
B4 Detection of the aberrantly spliced exon 1 - intron 1 htt mRNA in HD patient post mortem brain tissue and fibroblast lines
B4 HD 患者死后脑组织和成纤维细胞系中异常剪接的外显子 1 - 内含子 1 htt mRNA 的检测
- DOI:10.1136/jnnp-2016-314597.35
- 发表时间:2016
- 期刊:
- 影响因子:0
- 作者:Bates G
- 通讯作者:Bates G
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Gillian Bates其他文献
Gillian Bates的其他文献
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{{ truncateString('Gillian Bates', 18)}}的其他基金
Investigation of the mechanism by which huntingtin fragments are produced and their pathogenic relevance to Huntington's disease
研究亨廷顿片段的产生机制及其与亨廷顿病的致病相关性
- 批准号:
MR/L003627/2 - 财政年份:2016
- 资助金额:
$ 46.2万 - 项目类别:
Research Grant
Investigation of Heat shock Factor 1 as a Therapeutic Target for Huntington s Disease
热休克因子 1 作为亨廷顿病治疗靶点的研究
- 批准号:
G0801314/1 - 财政年份:2009
- 资助金额:
$ 46.2万 - 项目类别:
Research Grant
Identification and Cross-validation of Early Stage Phenotypes in Mouse Models of Huntington s disease
亨廷顿病小鼠模型早期表型的鉴定和交叉验证
- 批准号:
G0800846/1 - 财政年份:2009
- 资助金额:
$ 46.2万 - 项目类别:
Research Grant
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Molecular Mechanism of Huntingtin Misfolding and its Inhibition by Designed and Cellular Proteins
亨廷顿蛋白错误折叠的分子机制及其设计和细胞蛋白的抑制
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10317950 - 财政年份:2021
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Molecular Mechanism of Huntingtin Misfolding and its Inhibition by Designed and Cellular Proteins
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Defective DNA Damage Repair and Aberrant PARylation as a Mechanism of Mutant Huntingtin in Huntington's Disease
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Investigation of the mechanism by which huntingtin fragments are produced and their pathogenic relevance to Huntington's disease
研究亨廷顿片段的产生机制及其与亨廷顿病的致病相关性
- 批准号:
MR/L003627/2 - 财政年份:2016
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Investigating the Mechanism and Effect of Disease-Associated Increases in the Huntingtin Long 3'UTR Isoform
研究亨廷顿蛋白长 3UTR 亚型与疾病相关的增加的机制和影响
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Investigating the Mechanism and Effect of Disease-Associated Increases in the Huntingtin Long 3'UTR Isoform
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