Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice
Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice
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DOI：
10.1172/jci44867
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发表时间：
2011-02-01
影响因子：
15.9
通讯作者：
Lee, Virginia M. -Y.
中科院分区：
文献类型：
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作者：
Igaz, Lionel M.;Kwong, Linda K.;Lee, Virginia M. -Y.
肌萎缩侧索硬化症(ALS)和额颞叶变性(FTLD)的特点是脑和脊髓中的胞浆蛋白聚集体，其中包括TDP-43(TDP-43)。TDP-43通常定位于细胞核中，参与基因表达的调节，病理性的胞质聚集与核蛋白的耗尽有关。在这里，我们建立了前脑核定位信号缺陷的表达人TDP-43的转基因小鼠(hTDP-43-Delta NLS)，并将它们与表达WT hTDP-43的小鼠(hTDP-43-WT)进行比较，以确定细胞质错误定位的TDP-43对神经元活力的影响。HTDP-43-Delta NLS或hTDP-43-WT的表达导致选择性脆弱的前脑区神经元丢失，皮质脊髓束变性，运动痉挛，重现FTLD和原发性侧索硬化症的关键方面。在hTDP-43-Delta NLS小鼠中仅观察到罕见的胞浆磷酸化和泛素化的TDP-43包涵体，这表明胞质包涵体不是诱导神经元死亡所必需的。相反，hTDP-43和hTDP-43-Delta NLS表达的神经元的神经变性伴随着内源性小鼠TDP-43的戏剧性下调。此外，表达hTDP-43-Delta NLS的小鼠皮质神经元的基因表达发生了深刻的变化。我们的数据表明，内源性TDP-43核的扰动导致正常TDP-43功能和基因调控通路的丧失(S)，最终导致选择性易受影响的神经元变性。
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by cytoplasmic protein aggregates in the brain and spinal cord that include TAR-DNA binding protein 43 (TDP-43). TDP-43 is normally localized in the nucleus with roles in the regulation of gene expression, and pathological cytoplasmic aggregates are associated with depletion of nuclear protein. Here, we generated transgenic mice expressing human TDP-43 with a defective nuclear localization signal in the forebrain (hTDP-43-Delta NLS), and compared them with mice expressing WT hTDP-43 (hTDP-43-WT) to determine the effects of mislocalized cytoplasmic TDP-43 on neuronal viability. Expression of either hTDP-43-Delta NLS or hTDP-43-WT led to neuron loss in selectively vulnerable forebrain regions, corticospinal tract degeneration, and motor spasticity recapitulating key aspects of FTLD and primary lateral sclerosis. Only rare cytoplasmic phosphorylatecl and ubiquitinated TDP-43 inclusions were seen in hTDP-43-Delta NLS mice, suggesting that cytoplasmic inclusions were not required to induce neuronal death. Instead, neurodegeneration in hTDP-43 and hTDP-43-Delta NLS-expressing neurons was accompanied by a dramatic downregulation of the endogenous mouse TDP-43. Moreover, mice expressing hTDP-43-Delta NLS exhibited profound changes in gene expression in cortical neurons. Our data suggest that perturbation of endogenous nuclear TDP-43 results in loss of normal TDP-43 function(s) and gene regulatory pathways, culminating in degeneration of selectively vulnerable affected neurons.