Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease
Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease
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DOI：
10.1038/sj.cdd.4401221
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发表时间：
2003-06-01
影响因子：
12.4
通讯作者：
Tohyama, M
中科院分区：
文献类型：
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作者：
Manabe, T;Katayama, T;Tohyama, M
由早老素-2（PS2）基因转录本的第5号外显子跳跃产生的异常剪接亚型（PS2 V）是散发性阿尔茨海默病（AD）的诊断特征。我们发现PS2 V在人神经母细胞瘤SK-N-SH细胞中是缺氧诱导的。我们纯化了一个负责任的反式作用因子的基础上结合的外显子5片段。该因子被鉴定为高迁移率族A1 a蛋白（HMGA 1a;以前为HMG-I）。HMGA 1a与位于50剪接位点上游的外显子5上的特定序列结合。缺氧诱导HMGA 1a表达，并在内源性剪接因子SC 35的作用下在核斑点中积累。HMGA 1a的过表达产生PS2 V，但是PS2 V通过与对HMGA 1a具有强亲和力的U1 snRNP 70 K蛋白共转染而被抑制。HMGA 1a可以干扰U1 snRNP与50剪接位点的结合，并导致第5号外显子跳读。散发性AD患者脑组织中HMGA 1a水平显著升高。我们提出了一种新的散发性AD的机制，涉及HMGA 1a诱导的PS2前体mRNA的异常剪接，在没有任何突变的情况下。
The aberrant splicing isoform (PS2V), generated by exon 5 skipping of the Presenilin-2 (PS2) gene transcript, is a diagnostic feature of sporadic Alzheimer's disease ( AD). We found PS2V is hypoxia-inducible in human neuroblastoma SK-N-SH cells. We purified a responsible trans-acting factor based on its binding to an exon 5 fragment. The factor was identified as the high mobility group A1a protein (HMGA1a; formerly HMG-I). HMGA1a bound to a specific sequence on exon 5, located upstream of the 50 splice site. HMGA1a expression was induced by hypoxia and the protein was accumulated in the nuclear speckles with the endogenous splicing factor SC35. Overexpression of HMGA1a generated PS2V, but PS2V was repressed by cotransfection with the U1 snRNP 70K protein that has a strong affinity to HMGA1a. HMGA1a could interfere with U1 snRNP binding to the 50 splice site and caused exon 5 skipping. HMGA1a levels were significantly increased in the brain tissue from sporadic AD patients. We propose a novel mechanism of sporadic AD that involves HMGA1a-induced aberrant splicing of PS2 premRNA in the absence of any mutations.