Pathophysiological characterization of MERRF patient-specific induced neurons generated by direct reprogramming
Pathophysiological characterization of MERRF patient-specific induced neurons generated by direct reprogramming
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DOI：
10.1016/j.bbamcr.2019.02.010
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发表时间：
2019-05-01
影响因子：
5.1
通讯作者：
Sanchez-Alcazar, Jose A.
中科院分区：
文献类型：
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作者：
Villanueva-Paz, Marina;Povea-Cabello, Suleva;Sanchez-Alcazar, Jose A.
线粒体疾病是一组由全部或部分线粒体功能障碍引起的罕见异质遗传性疾病。它们可能是由核或线粒体 DNA (mtDNA) 突变引起的。 MERRF（红色纤维肌阵挛性癫痫）综合征是由 mtDNA 点突变引起的最常见线粒体疾病之一。主要是由mtDNA（MT-TK基因）的tRNA（Lys）（UUR）基因的m.8344A>G突变引起的。这种突变会影响 mtDNA 编码蛋白的翻译；因此，电子传递链 (ETC) 复合物的组装被破坏，导致线粒体呼吸功能下降。然而，由于缺乏适当的细胞模型，特别是在神经元等受该疾病影响最严重的细胞类型中，MERRF 综合征的分子发病机制仍然知之甚少。患者特异性诱导神经元 (iN) 源自真皮成纤维细胞，这些真皮成纤维细胞来自携带引起疾病的特定突变的不同个体。因此，患者特异性 iN 可以作为一种优秀的细胞模型来阐明 MERRF 综合征的机制。在这里，我们首次提出通过直接重编程从 MERRF 真皮成纤维细胞产生 iN，以及一系列病理生理学特征，可用于测试特定 mtDNA 突变对神经元的影响并筛选可以纠正表型的药物。
Mitochondrial diseases are a group of rare heterogeneous genetic disorders caused by total or partial mitochondrial dysfunction. They can be caused by mutations in nuclear or mitochondrial DNA (mtDNA). MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome is one of the most common mitochondrial disorders caused by point mutations in mtDNA. It is mainly caused by the m.8344A > G mutation in the tRNA(Lys) (UUR) gene of mtDNA (MT-TK gene). This mutation affects the translation of mtDNA encoded proteins; therefore, the assembly of the electron transport chain (ETC) complexes is disrupted, leading to a reduced mitochondrial respiratory function.However, the molecular pathogenesis of MERRF syndrome remains poorly understood due to the lack of appropriate cell models, particularly in those cell types most affected in the disease such as neurons. Patient-specific induced neurons (iNs) are originated from dermal fibroblasts derived from different individuals carrying the particular mutation causing the disease. Therefore, patient-specific iNs can be used as an excellent cell model to elucidate the mechanisms underlying MERRF syndrome. Here we present for the first time the generation of iNs from MERRF dermal fibroblasts by direct reprograming, as well as a series of pathophysiological characterizations which can be used for testing the impact of a specific mtDNA mutation on neurons and screening for drugs that can correct the phenotype.