Heterogeneous nuclear ribonucleoprotein E3 modestly activates splicing of tau exon 10 via its proximal downstream intron, a hotspot for frontotemporal dementia mutations.
Heterogeneous nuclear ribonucleoprotein E3 modestly activates splicing of tau exon 10 via its proximal downstream intron, a hotspot for frontotemporal dementia mutations.
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DOI：
10.1016/j.gene.2009.11.006
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发表时间：
2010-02-01
期刊：
影响因子：
3.5
通讯作者：
Andreadis A
中科院分区：
文献类型：
--
作者：
Wang Y;Gao L;Tse SW;Andreadis A
微管相关蛋白tau对哺乳动物神经系统中的正常神经元活动是重要的。聚集的tau蛋白是神经元缠结（NFT）的主要成分，NFT是存在于受神经退行性疾病（称为tau蛋白病）影响的人的大脑中的结构。Tau病包括阿尔茨海默病（AD）、额颞叶痴呆伴帕金森综合征（FTDP）和唐氏综合征（DS; 21三体）中观察到的早发性痴呆。成人特异性外显子10的剪接失调导致tau亚型的异常比例表达，导致FTDP。外显子10下游内含子的+3至+19位定义了一个热点：其中的点突变导致tau蛋白病。所有这些突变都增加了外显子10的包含，除了突变+19，其几乎完全排除了外显子10。为了研究DS和AD之间的tau连接，我们检查了位于21号染色体上的剪接因子对tau外显子10的影响。通过共转染、免疫共沉淀和RNAi构建体，我们发现其中之一hnRNPE 3（PCBP 3）通过与其近端下游内含子在位置+19附近相互作用适度激活外显子10的剪接。这些结果，再加上hnRNPE 3的发育概况，表明21号染色体上的剪接因子在神经退行性疾病与缠结中的致病作用，并在tau剪接与唐氏综合征的早发性痴呆之间建立了联系。
The microtubule-associated protein tau is important to normal neuronal activity in the mammalian nervous system. Aggregated tau is the major component of neurofibrillary tangles (NFTs), structures present in the brains of people affected by neurodegenerative diseases called tauopathies. Tauopathies include Alzheimer's disease (AD), frontotemporal dementia with Parkinsonism (FTDP) and the early onset dementia observed in Down syndrome (DS; trisomy 21). Splicing misregulation of adult-specific exon 10 results in expression of abnormal ratios of tau isoforms, leading to FTDP. Positions +3 to +19 of the intron downstream of exon 10 define a hotspot: point mutations in it result in tauopathies. All these mutations increase exon 10 inclusion except for mutation +19, which almost entirely excludes exon 10. To investigate the tau connection between DS and AD, we examined splicing factors located on chromosome 21 for their effect on tau exon 10. By co-transfections, co-immunoprecipitations and RNAi constructs, we discovered that one of them, hnRNPE3 (PCBP3), modestly activates splicing of exon 10 by interacting with its proximal downstream intron around position +19. These results, coupled with the developmental profile of hnRNPE3, suggest a pathogenic role for splicing factors on chromosome 21 in neurodegenerative diseases with tangles and create a connection between tau splicing and the early-onset dementia of Down syndrome.
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影响因子：
5.6
作者：
Kim, JH;Hahm, B;Jang, SK
通讯作者：
Jang, SK
影响因子：
4.8
作者：
Liu, Fei;Liang, Zhihou;Gong, Cheng-Xin
通讯作者：
Gong, Cheng-Xin
影响因子：
2.5
作者：
Ikegami, S;Harada, A;Hirokawa, N
通讯作者：
Hirokawa, N
影响因子：
14.5
作者：
Stanford, PM;Shepherd, CE;Schofield, PR
通讯作者：
Schofield, PR
DOI：
10.1007/978-0-387-77374-2_8
发表时间：
2007-01-01
期刊：
ALTERNATIVE SPLICING IN THE POSTGENOMIC ERA
影响因子：
--
作者：
Martinez-Contreras, Rebeca;Cloutier, Philippe;Chabot, Benoit
通讯作者：
Chabot, Benoit