Selective retinal ganglion cell loss and optic neuropathy in a humanized mouse model of familial dysautonomia.
Selective retinal ganglion cell loss and optic neuropathy in a humanized mouse model of familial dysautonomia.
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DOI：
10.1093/hmg/ddab359
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发表时间：
2022-06-04
影响因子：
3.5
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中科院分区：
文献类型：
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家族性自主神经功能障碍（FD）是一种常染色体隐性遗传性神经退行性疾病，由编码延长子复合蛋白1（ELP 1，也称为IKBKAP）的基因剪接突变引起。这种突变导致外显子20的组织特异性跳跃，并相应减少ELP 1蛋白，主要是在中枢和外周神经系统中。虽然FD患者具有由感觉和自主神经元的持续耗竭引起的复杂神经系统表型，但导致失明的进行性视力下降是该疾病最有问题的方面之一，因为它严重影响了他们的生活质量。为了更好地理解疾病机制以及测试FD靶向治疗的体内功效，我们最近产生了一种新的表型小鼠模型TgFD 9; IkbkapΔ20/flox。该小鼠表现出该疾病的大部分临床特征，并准确地再现了在FD患者中观察到的组织特异性剪接缺陷。由于迫切需要开发针对FD中视网膜变性的疗法，我们在此全面表征了该小鼠中视网膜表型的进展，并且我们证明了使用剪接调节剂化合物（SMC）BPN-15477校正视网膜中的ELP 1剪接缺陷是可能的。
Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease caused by a splicing mutation in the gene encoding Elongator complex protein 1 (ELP1, also known as IKBKAP). This mutation results in tissue-specific skipping of exon 20 with a corresponding reduction of ELP1 protein, predominantly in the central and peripheral nervous system. Although FD patients have a complex neurological phenotype caused by continuous depletion of sensory and autonomic neurons, progressive visual decline leading to blindness is one of the most problematic aspects of the disease, as it severely affects their quality of life. To better understand the disease mechanism as well as to test the in vivo efficacy of targeted therapies for FD, we have recently generated a novel phenotypic mouse model, TgFD9; IkbkapΔ20/flox. This mouse exhibits most of the clinical features of the disease and accurately recapitulates the tissue-specific splicing defect observed in FD patients. Driven by the dire need to develop therapies targeting retinal degeneration in FD, herein, we comprehensively characterized the progression of the retinal phenotype in this mouse, and we demonstrated that it is possible to correct ELP1 splicing defect in the retina using the splicing modulator compound (SMC) BPN-15477.
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影响因子：
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通讯作者：
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