Disease Modeling with Human Neurons Reveals LMNB1 Dysregulation Underlying DYT1 Dystonia
Disease Modeling with Human Neurons Reveals LMNB1 Dysregulation Underlying DYT1 Dystonia
复制标题
人类神经元疾病模型揭示了 DYT1 肌张力障碍背后的 LMNB1 失调
DOI：
10.1523/jneurosci.2507-20.2020
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发表时间：
2021-03-03
影响因子：
5.3
通讯作者：
Zhang, Chun-Li
中科院分区：
文献类型：
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作者：
Ding, Baojin;Tang, Yu;Zhang, Chun-Li
DYT1肌张力障碍是一种遗传性神经系统运动障碍，其特征是无法控制的肌肉收缩。它是由编码膜包埋ATP酶的基因Torsin A（TOR1A）的杂合突变引起的。虽然动物模型提供了对疾病机制的见解，但由于具有相同杂合突变的动物未能显示病理学，因此存在显著的物种依赖性差异。在这里，我们通过使用人类患者特异性胆碱能运动神经元（MN）来模拟DYT1，所述胆碱能运动神经元通过患者皮肤成纤维细胞的直接转化或诱导多能干细胞（iPSC）的分化产生。这些具有杂合性TOR1A突变的人MN显示出减少的神经突长度和分支、显著增厚的核纤层、破坏的核形态以及mRNA和蛋白质的核质转运（NCT）受损，而它们缺乏在动物模型中经常观察到的核周“泡”。此外，我们发现核纤层蛋白LMNB 1在DYT 1细胞中上调，并以胆碱能MN特异性方式表现出异常的亚细胞分布。LMNB 1的这种失调可以通过突变型TOR1A基因的异位表达或健康对照MN中内源性TOR1A的shRNA介导的下调来重现。有趣的是，LMNB 1的下调可以在很大程度上改善DYT 1 MN中的所有细胞缺陷。这些结果揭示了人类患者特异性神经元疾病建模的价值，并表明核纤层的关键组分LMNB 1的失调可能构成DYT 1病理学的主要分子机制。
DYT1 dystonia is a hereditary neurologic movement disorder characterized by uncontrollable muscle contractions. It is caused by a heterozygous mutation in Torsin A (TOR1A), a gene encoding a membrane-embedded ATPase. While animal models provide insights into disease mechanisms, significant species-dependent differences exist since animals with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-specific cholinergic motor neurons (MNs) that are generated through either direct conversion of patients' skin fibroblasts or differentiation of induced pluripotent stem cells (iPSCs). These human MNs with the heterozygous TOR1A mutation show reduced neurite length and branches, markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport (NCT) of mRNAs and proteins, whereas they lack the perinuclear "blebs" that are often observed in animal models. Furthermore, we uncover that the nuclear lamina protein LMNB1 is upregulated in DYT1 cells and exhibits abnormal subcellular distribution in a cholinergic MNs-specific manner. Such dysregulation of LMNB1 can be recapitulated by either ectopic expression of the mutant TOR1A gene or shRNA-mediated downregulation of endogenous TOR1A in healthy control MNs. Interestingly, downregulation of LMNB1 can largely ameliorate all the cellular defects in DYT1 MNs. These results reveal the value of disease modeling with human patient-specific neurons and indicate that dysregulation of LMNB1, a crucial component of the nuclear lamina, may constitute a major molecular mechanism underlying DYT1 pathology.