Disulfide cross-linked multimers of TDP-43 and spinal motoneuron loss in a TDP-43(A315T) ALS/FTD mouse model.
Disulfide cross-linked multimers of TDP-43 and spinal motoneuron loss in a TDP-43(A315T) ALS/FTD mouse model.
复制标题
DOI：
10.1038/s41598-017-14399-5
复制
发表时间：
2017-10-27
影响因子：
4.6
通讯作者：
Matus S
中科院分区：
文献类型：
--
作者：
Bargsted L;Medinas DB;Martínez Traub F;Rozas P;Muñoz N;Nassif M;Jerez C;Catenaccio A;Court FA;Hetz C;Matus S
焦油DNA结合蛋白43（TDP-43）是存在于大多数肌萎缩侧索硬化（ALS）和额颞叶痴呆（FTD）病例的神经组织中的泛素化蛋白包涵体的主要成分。先前的研究描述了一种TDP-43 A315 T转基因小鼠模型，该模型在没有蛋白质聚集或显著运动神经元损失的情况下发生进行性运动功能障碍，质疑其研究ALS的有效性。在这里，我们使用一系列测试和生物化学方法进一步表征了TDP-43 A315 T小鼠的疾病过程。我们证实，TDP-43突变小鼠的运动能力受损，伴随着进行性体重减轻。观察到性别之间的寿命存在显著差异，女性比男性存活时间更长。脊髓组织学分析显示运动神经元明显丢失，伴有轴突变性、星形胶质细胞增生和小胶质细胞活化。重要的是，在TDP-43突变小鼠中观察到的组织病理学变化与在突变SOD 1小鼠中观察到的一些特征性变化相似。出乎意料的是，我们鉴定出在皮质和脊髓组织中存在不同种类的二硫键依赖性TDP-43聚集体。总体而言，这项研究表明，TDP-43 A315 T转基因小鼠的关键特征与ALS的关键方面相似，突出了其与研究疾病发病机制的相关性。
Tar DNA binding protein 43 (TDP-43) is the principal component of ubiquitinated protein inclusions present in nervous tissue of most cases of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies described a TDP-43A315T transgenic mouse model that develops progressive motor dysfunction in the absence of protein aggregation or significant motoneuron loss, questioning its validity to study ALS. Here we have further characterized the course of the disease in TDP-43A315T mice using a battery of tests and biochemical approaches. We confirmed that TDP-43 mutant mice develop impaired motor performance, accompanied by progressive body weight loss. Significant differences were observed in life span between genders, where females survived longer than males. Histopathological analysis of the spinal cord demonstrated a significant motoneurons loss, accompanied by axonal degeneration, astrogliosis and microglial activation. Importantly, histopathological alterations observed in TDP-43 mutant mice were similar to some characteristic changes observed in mutant SOD1 mice. Unexpectedly, we identified the presence of different species of disulfide-dependent TDP-43 aggregates in cortex and spinal cord tissue. Overall, this study indicates that TDP-43A315T transgenic mice develop key features resembling key aspects of ALS, highlighting its relevance to study disease pathogenesis.
登录
查看更多内容
影响因子：
38.1
作者：
Chen-Plotkin, Alice S.;Lee, Virginia M. -Y.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
7
作者：
Elvira, G;Wasiak, S;Sossin, WS
通讯作者：
Sossin, WS
影响因子：
5.4
作者：
Buratti, Emanuele;De Conti, Laura;Baralle, Francisco
通讯作者：
Baralle, Francisco
DOI：
10.1073/pnas.0902505106
发表时间：
2009-05-12
影响因子：
11.1
作者：
Karch, Celeste M.;Prudencio, Mercedes;Borchelt, David R.
通讯作者：
Borchelt, David R.
影响因子：
12.7
作者：
Ke, Yazi D.;van Hummel, Annika;Ittner, Lars M.
通讯作者：
Ittner, Lars M.