近日,，美國(guó)賓夕法尼亞大學(xué)醫(yī)學(xué)院神經(jīng)退行性疾病研究中心的科學(xué)家通過(guò)研究，首次找到解釋TDP-43蛋白發(fā)生變異時(shí)是如何導(dǎo)致神經(jīng)細(xì)胞死亡的直接證據(jù),。他們?cè)凇杜R床研究期刊》上報(bào)告了這一發(fā)現(xiàn),。
TDP-43蛋白是一種RNA結(jié)合蛋白，當(dāng)它發(fā)生變異時(shí),，會(huì)導(dǎo)致肌萎縮側(cè)索硬化癥（ALS,，亦稱“漸凍癥”）和額顳葉變性（FTLD）兩種疾病的產(chǎn)生。TDP-43于2006年被首次發(fā)現(xiàn)是ALS和FTLD的主要致病蛋白,，發(fā)現(xiàn)者正好是領(lǐng)導(dǎo)這項(xiàng)最新研究的Virginia M.-Y. Lee和John Q. Trojanowski兩位教授當(dāng)時(shí)所帶領(lǐng)的課題組,。
以往有關(guān)TDP-43的研究認(rèn)為神經(jīng)細(xì)胞的死亡原因有兩種：一是，TDP-43所屬蛋白團(tuán)本身具有對(duì)神經(jīng)細(xì)胞的毒性,；二是,，當(dāng)TDP-43被蛋白團(tuán)包裹后，細(xì)胞中具有正常功能的TDP-43蛋白將減少,，而一般情況下,，細(xì)胞對(duì)TDP-43的數(shù)量是有精確控制的——TDP-43太多或太少都會(huì)出問(wèn)題。一旦TDP-43功能喪失,，將對(duì)疾病的調(diào)控產(chǎn)生嚴(yán)重影響,。
在這項(xiàng)最新研究中，科學(xué)家通過(guò)將人類TDP-43的突變體和正常體這兩種蛋白植入小鼠體內(nèi)進(jìn)行對(duì)比,，發(fā)現(xiàn)兩種情況均導(dǎo)致小鼠前腦敏感區(qū)的神經(jīng)細(xì)胞數(shù)量減少,、脊髓束部分退化、肌肉發(fā)生抽搐,。這些特征與FTLD的關(guān)鍵癥狀吻合,，也符合ALS的一種被稱為原發(fā)性側(cè)索硬化（primary lateral sclerosis）的子類型所示癥狀。
研究人員認(rèn)為,，小鼠自身TDP-43數(shù)量受到人類TDP-43突變體植入的影響而減少,，其功能也因人類TDP-43的過(guò)度表達(dá)而被阻礙,，由此才最終導(dǎo)致神經(jīng)細(xì)胞死亡的，并且研究人員在小鼠細(xì)胞內(nèi)幾乎沒(méi)有觀察到包裹了TDP-43的蛋白團(tuán),，因此他們認(rèn)為,，有關(guān)蛋白團(tuán)是導(dǎo)致神經(jīng)細(xì)胞死亡的根本原因的這種說(shuō)法并不正確。不過(guò)他們還不清楚為什么小鼠細(xì)胞內(nèi)沒(méi)有出現(xiàn)這種蛋白團(tuán),。
下一步,，研究人員將尋找能夠調(diào)控TDP-43的特定基因以及研究mRNA在剪接過(guò)程中是如何修正基因的非正常表達(dá)的。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
