Chromosomal instability during neurogenesis in Huntington's disease
Chromosomal instability during neurogenesis in Huntington's disease
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DOI：
10.1242/dev.156844
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发表时间：
2018-01-01
期刊：
影响因子：
4.6
通讯作者：
Brivanlou, Ali H.
中科院分区：
文献类型：
--
作者：
Ruzo, Albert;Croft, Gist F.;Brivanlou, Ali H.
亨廷顿病(HD)是一种由亨廷顿基因(HTT)中CAG重复序列扩增引起的致死性神经退行性疾病。其发病机制和HTT的正常功能尚不清楚。为了在人类中建立HD模型，我们设计了一系列等位基因的等基因人类胚胎干细胞(HESC)系，其CAG重复长度逐渐增加。这些品系的神经分化揭示了一种新的发育HD表型：巨大的多核端脑神经元的出现与CAG重复长度成正比，这是由染色体不稳定和多轮DNA复制中胞质分裂失败所产生的。我们得出结论，发育过程中神经发生的中断是HD发病机制中一个重要的、未被认识的方面。为了研究正常HTT蛋白的功能，我们构建了HTT+/-和HTT-/-系。令人惊讶的是，同样的表型出现在HTT-/-系中，但不是HTT+/-系。我们的结论是，HD是一种发育障碍，其特征是染色体不稳定，损害神经发生，与流行的毒性功能获得假说相反，HD代表一种遗传显性-负性功能丧失。发育改变的后果应被视为HD治疗的新靶点。
Huntington's disease (HD) is a fatal neurodegenerative disease caused by expansion of CAG repeats in the Huntingtin gene (HTT). Neither its pathogenic mechanisms nor the normal functions of HTT are well understood. To model HD in humans, we engineered a genetic allelic series of isogenic human embryonic stem cell (hESC) lines with graded increases in CAG repeat length. Neural differentiation of these lines unveiled a novel developmental HD phenotype: the appearance of giant multinucleated telencephalic neurons at an abundance directly proportional to CAG repeat length, generated by a chromosomal instability and failed cytokinesis over multiple rounds of DNA replication. We conclude that disrupted neurogenesis during development is an important, unrecognized aspect of HD pathogenesis. To address the function of normal HTT protein we generated HTT+/- and HTT-/- lines. Surprisingly, the same phenotype emerged in HTT-/- but not HTT+/- lines. We conclude that HD is a developmental disorder characterized by chromosomal instability that impairs neurogenesis, and that HD represents a genetic dominant-negative loss of function, contrary to the prevalent gain-of-toxic-function hypothesis. The consequences of developmental alterations should be considered as a new target for HD therapies.