Phosphatidylserine increases IKBKAP levels in a humanized knock-in IKBKAP mouse model
Phosphatidylserine increases IKBKAP levels in a humanized knock-in IKBKAP mouse model
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DOI：
10.1093/hmg/ddt126
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发表时间：
2013-07-15
影响因子：
3.5
通讯作者：
Ast, Gil
中科院分区：
文献类型：
--
作者：
Bochner, Ron;Ziv, Yael;Ast, Gil
家族性自主神经功能障碍（FD）是一种严重的神经退行性遗传疾病，仅限于德系犹太人。FD患者中最常见的突变是IKBKAP基因内含子20第6位的T至C转换。这种突变以组织特异性方式引起外显子20的异常跳跃，导致神经系统中IB激酶复合物相关蛋白（IKAP）蛋白的减少。我们建立了一个纯合的人源化小鼠品系携带人类外显子20和它的两个侧翼内含子;第3内含子具有在FD患者的IKBKAP基因中观察到的转换。虽然我们的FD人源化小鼠没有显示FD症状，但这些小鼠中IKBKAP的独特组织特异性剪接模式使我们能够评估治疗对基因表达和外显子20剪接的影响。FD小鼠补充了磷脂酰丝氨酸（PS），这是一种安全的食品补充剂，可增加FD患者产生的细胞系中IKBKAP的mRNA和蛋白质水平。在这里，我们证明了PS治疗增加了FD小鼠各种组织中IKBAKP mRNA和IKAP蛋白水平，而不影响外显子20包含水平。我们还观察到与转录调控和发育过程相关的基因在PS处理的小鼠大脑中上调。因此，PS有望用于FD的治疗。
Familial dysautonomia (FD) is a severe neurodegenerative genetic disorder restricted to the Ashkenazi Jewish population. The most common mutation in FD patients is a T-to-C transition at position 6 of intron 20 of the IKBKAP gene. This mutation causes aberrant skipping of exon 20 in a tissue-specific manner, leading to reduction of the IB kinase complex-associated protein (IKAP) protein in the nervous system. We established a homozygous humanized mouse strain carrying human exon 20 and its two flanking introns; the 3 intron has the transition observed in the IKBKAP gene of FD patients. Although our FD humanized mouse does not display FD symptoms, the unique, tissue-specific splicing pattern of the IKBKAP in these mice allowed us to evaluate the effect of therapies on gene expression and exon 20 splicing. The FD mice were supplemented with phosphatidylserine (PS), a safe food supplement that increases mRNA and protein levels of IKBKAP in cell lines generated from FD patients. Here we demonstrated that PS treatment increases IKBAKP mRNA and IKAP protein levels in various tissues of FD mice without affecting exon 20 inclusion levels. We also observed that genes associated with transcription regulation and developmental processes were up-regulated in the cerebrum of PS-treated mice. Thus, PS holds promise for the treatment of FD.