Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability
Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability
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DOI：
10.1073/pnas.1202922109
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发表时间：
2012-04-10
影响因子：
11.1
通讯作者：
Chandran, Siddharthan
中科院分区：
文献类型：
--
作者：
Bilican, Bilada;Serio, Andrea;Chandran, Siddharthan
反式反应DNA结合蛋白（TDP-43）是肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD-TDP）的一个亚组中的主要疾病蛋白。家族性ALS中编码TDP-43（TARDBP）的基因突变的鉴定证实了TDP-43的错误积累与神经变性之间的机制联系，并提供了通过使用诱导多能干细胞（iPSC）研究由患者成纤维细胞产生的人类神经元中TDP-43蛋白质病的机会。在这里，我们报告了携带TDP-43 M337 V突变的iPSC的产生及其向神经元和功能性运动神经元的分化。突变的神经元具有升高的可溶性和洗涤剂抗性TDP-43蛋白水平，在纵向研究中存活率降低，并且对PI 3 K通路的拮抗作用的脆弱性增加。我们得出结论，TDP-43在人类神经元中的生理水平的表达足以揭示突变特异性细胞自主表型，并强烈支持这种方法用于疾病机制的研究和药物筛选。
Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 (TARDBP) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation and their differentiation into neurons and functional motor neurons. Mutant neurons had elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the PI3K pathway. We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell-autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening.