Alternated splicing of tau in development and neurodegenerating disorders with dementia.

发育中 tau 蛋白的交替剪接和神经退行性疾病(痴呆)。

基本信息

  • 批准号:
    16590841
  • 负责人:
  • 金额:
    $ 1.92万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 财政年份:
    2004
  • 资助国家:
    日本
  • 起止时间:
    2004 至 2005
  • 项目状态:
    已结题

项目摘要

Tau is one of the microtubule-associated proteins (MAPs) that play a role in promoting the polymerization and stabilization of neuronal microtubules and is involved in both the maintenance of the neuronal cytoskeleton and axonal transport. Human tau is encoded by a single gene (TAU) on chromosome 17 from which six isoforms are produced in the adult brain by alternative splicing of exons 2, 3 and 10. Tau exon 10 (E10) encodes the second microtubule-binding domain, and alternative splicing of this exon results in isoforms with three (E10-) or four (E10+) microtubule-binding domains referred to as three-repeat tau (3R-tau) and four-repeat tau (4R-tau), respectively. 4R-tau binds microtubules more avidly than 3R-tau due to its additional microtubule-binding domain encoded with E10. In human brains, only 3R-tau is expressed in the fetal stage while both 3R-tau and 4R-tau are expressed in a ratio of approximately 1:1 in the adult stage. In contrast, rodent brains express only 3R-tau in fetal and neonatal stages and only 4R-tau in the adult stage. Some mutations of the TAU gene found in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) have been shown to affect alternative splicing of E10 and to thereby increase or decrease the ratio of 3R-tau to 4R-tau. Thus, as splicing of mouse E10 is different from human E10, the comparison of two genomic sequences is expected to provide a useful information. Genomic fragments were isolated from mouse genome libraries and compared with human sequence. We identified a new element in mouse intron 10 (I10) to suppress E10 splicing, which was located just after the stem-loop region previously proposed in human sequence and found to potentially form another stem-loop. Human I10 with a mutation (+29G to A) causing a decreased E10 splicing was also predicted to form similar double stem-loop, suggesting that this element is universally involved in regulation of E10 splicing.
Tau是微管相关蛋白(MAPs)之一,在促进神经元微管的聚合和稳定中发挥作用,参与维持神经元细胞骨架和轴突运输。人类tau基因由17号染色体上的单个基因(TAU)编码,在成人脑中通过外显子2、3和10的交替剪接产生六种亚型。tau外显子10(E10)编码第二微管结合域,该外显子的选择性剪接导致三个(E10-)或四个(E10+)微管结合域的异构体,分别称为三重复tau(3R-tau)和四重复tau(4R-tau)。4R-tau与微管的结合比3R-tau更强烈,这是因为其额外的微管结合结构域与E10编码。在人脑中,胎儿期仅有3R-tau的表达,而成人期3R-tau和4R-tau的表达比例约为1:1。相比之下,啮齿动物的大脑在胎儿和新生儿阶段只表达3R-tau,在成体阶段只表达4R-tau。在与17号染色体连锁的帕金森病患者中发现的一些TAU基因突变已被证明影响E10的选择性剪接,从而增加或减少3R-tau与4R-tau的比率。因此,由于小鼠E10的剪接不同于人类E10,两个基因组序列的比较有望提供有用的信息。从小鼠基因组文库中分离基因组片段,并与人类序列进行比较。我们在小鼠内含子10(I10)中发现了一个新的元件来抑制E10剪接,该元件位于先前在人类序列中提出的茎环区域之后,并发现有可能形成另一个茎环。具有导致E10剪接减少的突变(+29G到A)的人I10也被预测形成类似的双茎环,这表明该元件普遍参与调节E10剪接。

项目成果

期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Regulation of tau exon 10 splicing by a double stem-loop structure in mouse intron 10
小鼠内含子 10 中双茎环结构对 tau 外显子 10 剪接的调节
  • DOI:
  • 发表时间:
    2005
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Yamashita;T.;Tomiyama;T.;Li;Q.;Numata;H.;Mori;H
  • 通讯作者:
    H
Amyloid beta peptide-induced cerebral neuronal loss is mediated by caspase-3 in vivo
Amyloid beta peptide-induced cerebral neuronal loss is mediated by casuase-3 in vivo.
淀粉样β肽诱导的脑神经元损失是由体内casuase-3介导的。
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TAKUMA Hiroshi其他文献

TAKUMA Hiroshi的其他文献

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{{ truncateString('TAKUMA Hiroshi', 18)}}的其他基金

The therapeutic strategy for amyotrophic lateral sclerosis by elucidation and removal of accumulated protein-cleaving factors
通过阐明和去除累积的蛋白切割因子来治疗肌萎缩侧索硬化症
  • 批准号:
    16K09681
  • 财政年份:
    2016
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The strategy for treatment based on the association cascade with the amyotrophic lateral sclerosis causative genes and RNA editing enzyme
基于肌萎缩侧索硬化症致病基因和RNA编辑酶关联级联的治疗策略
  • 批准号:
    25461266
  • 财政年份:
    2013
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Involvement of RNA-editing enzyme and multi-factor to motor neuron death in patients with sporadic amyotrophic lateral sclerosis
RNA编辑酶和多因素与散发性肌萎缩侧索硬化症患者运动神经元死亡的关系
  • 批准号:
    21591071
  • 财政年份:
    2009
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Screening for new substrate and development of bio-marker for RNA editing enzyme in sporadic amyotrophic lateral sclerosis
散发性肌萎缩侧索硬化症RNA编辑酶新底物的筛选及生物标志物的开发
  • 批准号:
    19599003
  • 财政年份:
    2007
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A study for the contribution of RNA editing abnormality in sporadic Alzheimer's disease.
一项关于 RNA 编辑异常在散发性阿尔茨海默病中的作用的研究。
  • 批准号:
    13670662
  • 财政年份:
    2001
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Time Budget Survey of University Researchers
大学研究人员时间预算调查
  • 批准号:
    06306009
  • 财政年份:
    1994
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for Co-operative Research (A)
INVESTIGATION OF ATOM IMAGING BY ELECTRIC FIELD
电场原子成像研究
  • 批准号:
    04402010
  • 财政年份:
    1992
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (A)
EXCIMER FORMATION AND RELUXATION STUDIED BY CROSSED MOLECULAR BEAM EXPERIMENT
交叉分子束实验研究准分子形成和回流
  • 批准号:
    62460038
  • 财政年份:
    1987
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)
Study on Ultra-high Frequency-Stabilization Techniques of Tunable Dye Lasers
可调谐染料激光器超高频稳频技术研究
  • 批准号:
    63043024
  • 财政年份:
    1987
  • 资助金额:
    $ 1.92万
  • 项目类别:
    Grant-in-Aid for Overseas Scientific Research

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了解 FTDP-17 突变对人类 tau 环状 RNA 形成和功能的影响,以制定治疗方案
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