科学家揭示亨廷顿病新机制


亨廷顿病(即亨廷顿舞蹈病,HD)是由亨廷顿基因(HTTT)中CAG重复扩增引起的致命性神经退行性疾病。来自洛克菲勒大学的研究人员首次设计了一种模拟患亨廷顿病的人类胚胎干细胞(human embryonic stem cell,hESC)模型,研究于1月29日发表在《Development》杂志中,他们发现在发育过程中表现异常的神经元可能是HD发病机制中最重要的线索。

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HUMAN DEVELOPMENT
Chromosomal instability during neurogenesis in Huntington's disease

ABSTRACT
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.

翻译如下:
人类发展
亨廷顿舞蹈病神经发展过程中的染色体不稳定性

摘要
亨廷顿病(即亨廷顿舞蹈病,HD)是由亨廷顿基因(HTTT)中CAG重复扩增引起的致命性神经退行性疾病。HTT的致病机制和正常功能都没有被很好地理解。为了建立人类HD模型,我们设计了遗传等位基因系列,具有递增的CAG重复长度的同种人类胚胎干细胞(hESC)系。这些细胞系的神经分化揭示了一种新的发展HD表型:出现巨大的多核远端神经元,其数量与CAG重复长度成正比,这是由染色体的不稳定性和多轮DNA复制中失败的细胞质分裂导致的。我们推断出:在发育过程中被破坏的神经形成是HD发病机制中一个重要的、未被认识到的方面。为了处理正常HTT蛋白的功能,我们生成了HTT +/-和HTT - / -系。令人惊讶的是,相同的表型出现在HTT - / -而不是HTT +/-系。我们得出这样的结论:HD是一种以染色体不稳定为特征的发育障碍,其损害神经形成,并且HD代表遗传显性失活的功能,与普遍的毒性功能假说相反。发育改变的结果应被视为HD治疗的新目标。

(本文内容转载自:dev.biologists.org

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