Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope
Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope
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DOI：
10.1016/j.neuron.2005.11.010
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发表时间：
2005-12-22
期刊：
影响因子：
16.2
通讯作者：
Dauer, WT
中科院分区：
文献类型：
--
作者：
Goodchild, RE;Kim, CE;Dauer, WT
许多遗传病的一个神秘特征是，广泛表达的基因突变会导致组织特异性疾病。一个例子是DYT1肌张力障碍，这是一种由TorsinA编码基因的框内缺失(Delta Gag)引起的神经发育疾病。在这里，我们显示了TorsinA基因缺失(Tor1a(-/-))和纯合子疾病突变“敲门”小鼠(Tor1a(Delta gag/Delta gag))的神经细胞都含有严重异常的核膜，尽管非神经细胞类型看起来正常。这些膜异常发生在迁移后的胚胎神经元中，随后随着神经元的进一步成熟而恶化，这一发现引发了DYT1肌张力障碍的发育依赖性。这些观察结果表明，神经元对核膜定位的torsinA功能有独特的要求，并提示这种活性的丧失是DYT1肌张力障碍发病机制中的一个关键分子事件。
An enigmatic feature of many genetic diseases is that mutations in widely expressed genes cause tissue-specific illness. One example is DYT1 dystonia, a neurodevelopmental disease caused by an in-frame deletion (Delta gag) in the gene encoding torsinA. Here we show that neurons from both torsinA null (Tor1a(-/-)) and homozygous disease mutant "knockin" mice (Tor1a(Delta gag/Delta gag)) contain severely abnormal nuclear membranes, although non-neuronal cell types appear normal. These membrane abnormalities develop in postmigratory embryonic neurons and subsequently worsen with further neuronal maturation, a finding evocative of the developmental dependence of DYT1 dystonia. These observations demonstrate that neurons have a unique requirement for nuclear envelope localized torsinA function and suggest that loss of this activity is a key molecular event in the pathogenesis of DYT1 dystonia.