Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-β accumulation modifier
Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-β accumulation modifier
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DOI：
10.1073/pnas.1307345111
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发表时间：
2014-02-18
影响因子：
11.1
通讯作者：
Takeda, Masatoshi
中科院分区：
文献类型：
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作者：
Morihara, Takashi;Hayashi, Noriyuki;Takeda, Masatoshi
阿尔茨海默病（AD）的特征是β淀粉样蛋白（A β）的积累。然而，控制这一过程的基因仍然难以捉摸。为此，我们将不同的小鼠品系与转录组学相结合，直接鉴定疾病相关基因。我们发现具有DBA/2遗传背景的AD模型小鼠（APP-Tg）与SJL和C57BL/6小鼠相比，A β积累水平显著降低。然后，我们应用脑转录组学来揭示DBA/2中抑制A β积累的基因。为了避免检测到A β的继发性影响基因，我们使用无A β病理的非tg小鼠，并选择DBA/2小鼠中不同表达的候选基因。对具有混合遗传背景的APP-Tg小鼠的转录组分析显示，激酶蛋白轻链-1 （Klc1）是A β修饰子，表明细胞内运输在A β积累中的作用。在这些APP-Tg小鼠中，A β水平与Klc1剪接变体E的表达水平和Klc1基因型相关。在人类中，与未受影响的个体相比，AD患者脑和淋巴细胞中KLC1变异体E的表达水平明显更高。最后，神经母细胞瘤细胞的功能分析显示，KLC1变体E的过表达或敲低分别增加或减少A β的产生。KLC1变异E的鉴定表明，细胞内运输功能障碍是a β病理的一个致病因素。这种独特的小鼠品系和具有转录组学的模型小鼠的组合有望用于研究其他复杂疾病的遗传机制。
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (A beta). The genes that govern this process, however, have remained elusive. To this end, we combined distinct mouse strains with transcriptomics to directly identify disease-relevant genes. We show that AD model mice (APP-Tg) with DBA/2 genetic backgrounds have significantly lower levels of A beta accumulation compared with SJL and C57BL/6 mice. We then applied brain transcriptomics to reveal the genes in DBA/2 that suppress A beta accumulation. To avoid detecting secondarily affected genes by A beta, we used non-Tg mice in the absence of A beta pathology and selected candidate genes differently expressed in DBA/2 mice. Additional transcriptome analysis of APP-Tg mice with mixed genetic backgrounds revealed kinesin light chain-1 (Klc1) as an A beta modifier, indicating a role for intracellular trafficking in A beta accumulation. A beta levels correlated with the expression levels of Klc1 splice variant E and the genotype of Klc1 in these APP-Tg mice. In humans, the expression levels of KLC1 variant E in brain and lymphocyte were significantly higher in AD patients compared with unaffected individuals. Finally, functional analysis using neuroblastoma cells showed that overexpression or knockdown of KLC1 variant E increases or decreases the production of A beta, respectively. The identification of KLC1 variant E suggests that the dysfunction of intracellular trafficking is a causative factor of A beta pathology. This unique combination of distinct mouse strains and model mice with transcriptomics is expected to be useful for the study of genetic mechanisms of other complex diseases.