近日，美国宾夕法尼亚大学医学院神经退行性疾病研究中心的科学家通过研究，首次找到解释TDP-43蛋白发生变异时是如何导致神经细胞死亡的直接证据。他们在《临床研究期刊》上报告了这一发现。
TDP-43蛋白是一种RNA结合蛋白，当它发生变异时，会导致肌萎缩侧索硬化症（ALS，亦称“渐冻症”）和额颞叶变性（FTLD）两种疾病的产生。TDP-43于2006年被首次发现是ALS和FTLD的主要致病蛋白，发现者正好是领导这项最新研究的Virginia M.-Y. Lee和John Q. Trojanowski两位教授当时所带领的课题组。
以往有关TDP-43的研究认为神经细胞的死亡原因有两种：一是，TDP-43所属蛋白团本身具有对神经细胞的毒性；二是，当TDP-43被蛋白团包裹后，细胞中具有正常功能的TDP-43蛋白将减少，而一般情况下，细胞对TDP-43的数量是有精确控制的——TDP-43太多或太少都会出问题。一旦TDP-43功能丧失，将对疾病的调控产生严重影响。
在这项最新研究中，科学家通过将人类TDP-43的突变体和正常体这两种蛋白植入小鼠体内进行对比，发现两种情况均导致小鼠前脑敏感区的神经细胞数量减少、脊髓束部分退化、肌肉发生抽搐。这些特征与FTLD的关键症状吻合，也符合ALS的一种被称为原发性侧索硬化（primary lateral sclerosis）的子类型所示症状。
研究人员认为，小鼠自身TDP-43数量受到人类TDP-43突变体植入的影响而减少，其功能也因人类TDP-43的过度表达而被阻碍，由此才最终导致神经细胞死亡的，并且研究人员在小鼠细胞内几乎没有观察到包裹了TDP-43的蛋白团，因此他们认为，有关蛋白团是导致神经细胞死亡的根本原因的这种说法并不正确。不过他们还不清楚为什么小鼠细胞内没有出现这种蛋白团。
下一步，研究人员将寻找能够调控TDP-43的特定基因以及研究mRNA在剪接过程中是如何修正基因的非正常表达的。（生物谷Bioon.com）
生物谷推荐原文出处：
J Clin Invest. doi:10.1172/JCI44867.
Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice
Lionel M. Igaz, Linda K. Kwong, Edward B. Lee, Alice Chen-Plotkin, Eric Swanson, Travis Unger, Joe Malunda, Yan Xu, Matthew J. Winton, John Q. Trojanowski and Virginia M.-Y. Lee
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-ΔNLS), 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-ΔNLS 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 phosphorylated and ubiquitinated TDP-43 inclusions were seen in hTDP-43-ΔNLS mice, suggesting that cytoplasmic inclusions were not required to induce neuronal death. Instead, neurodegeneration in hTDP-43 and hTDP-43-ΔNLS–expressing neurons was accompanied by a dramatic downregulation of the endogenous mouse TDP-43. Moreover, mice expressing hTDP-43-ΔNLS 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.
