An SRp75/hnRNPG complex interacting with hnRNPE2 regulates the 5' splice site of tau exon 10, whose misregulation causes frontotemporal dementia.
An SRp75/hnRNPG complex interacting with hnRNPE2 regulates the 5' splice site of tau exon 10, whose misregulation causes frontotemporal dementia.
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DOI：
10.1016/j.gene.2011.06.020
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发表时间：
2011-10-10
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;Wang J;Gao L;Stamm S;Andreadis A
Tau是一种神经元特异性微管相关蛋白，在建立神经元极性和维持轴突细胞骨架中起重要作用。聚集的tau蛋白是神经原纤维缠结（nft）的主要成分，这种结构存在于被称为tau病的神经退行性疾病患者的大脑中。tau病变包括阿尔茨海默病（AD）、额颞叶痴呆伴帕金森病（FTDP-17）、唐氏综合征（DS； 21三体）中观察到的早发性痴呆以及1型肌强直性营养不良（DM1）的痴呆成分。编码微管结合域的成人特异性外显子10的剪接错误调节导致tau亚型的异常比例表达，从而导致FTDP-17。外显子10下游的内含子位置3至19定义了剪接调控的热点：该区域在人类和啮齿动物之间存在分歧，并且该区域内的点突变导致tau病变。在这项研究中，我们研究了3种外显子10剪接的调节因子：富含丝氨酸/精氨酸的蛋白SRp75和异质核核糖核蛋白hnRNPG和hnRNPE2。SRp75和hnRNPG抑制外显子10的剪接，而hnRNPE2激活剪接。通过共转染、共免疫沉淀和RNAi，我们发现SRp75在FTDP-17热点区域与tau外显子10的近端下游内含子结合；hnRNPG和hnRNPE2与SRp75相互作用。因此，FTDP突变体中增加的外显子10包含可能是由于SRp75结合减弱。这项工作为tau基因的剪接调节提供了见解，并为纠正由外显子10的比例变化引起的tau病的不平衡提供了可能的策略。
Tau is a neuronal-specific microtubule-associated protein that plays an important role in establishing neuronal polarity and maintaining the axonal cytoskeleton. 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-17), the early onset dementia observed in Down syndrome (DS; trisomy 21) and the dementia component of myotonic dystrophy type 1 (DM1). Splicing misregulation of adult-specific exon 10, which codes for a microtubule binding domain, results in expression of abnormal ratios of tau isoforms, leading to FTDP-17. Positions 3 to 19 of the intron downstream of exon 10 define a hotspot of splicing regulation: the region diverges between humans and rodents, and point mutations within it result in tauopathies. In this study, we investigated three regulators of exon 10 splicing: serine/arginine-rich protein SRp75 and heterogeneous nuclear ribonucleoproteins hnRNPG and hnRNPE2. SRp75 and hnRNPG inhibit splicing of exon 10 whereas hnRNPE2 activates it. Using co-transfections, co-immunoprecipitations and RNAi we discovered that SRp75 binds to the proximal downstream intron of tau exon 10 at the FTDP-17 hotspot region; and that hnRNPG and hnRNPE2 interact with SRp75. Thus, increased exon 10 inclusion in FTDP mutants may arise from weakened SRp75 binding. This work provides insights into the splicing regulation of the tau gene and into possible strategies for correcting the imbalance in tauopathies caused by changes in the ratio of exon 10.
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影响因子：
2.5
作者：
Ikegami, S;Harada, A;Hirokawa, N
通讯作者：
Hirokawa, N
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
影响因子：
4.8
作者：
Heinrich, Bettina;Zhang, Zhaiyi;Stamm, Stefan
通讯作者：
Stamm, Stefan
DOI：
10.1016/j.bbadis.2008.09.017
发表时间：
2009-01
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Tazi J;Bakkour N;Stamm S
通讯作者：
Stamm S
tau外显子10替代剪接和tauopathies。
影响因子：
15.1
作者：
Liu, Fei;Gong, Cheng-Xin
通讯作者：
Gong, Cheng-Xin