Mislocalization of the TAR DNA-binding protein 43 (TDP-43) from the nucleus to the cytoplasm is a common feature of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The downstream in vivo cellular effects of this mislocalization are not well understood. To investigate the impact of mislocalized TDP-43 on neuronal cell bodies, axons and axonal terminals, we utilized the mouse visual system to create a new model of TDP-43 proteinopathy. Mouse (C57BL/6J) retinal ganglion cells (RGCs) were transduced with GFP-tagged human wildtype TDP-43 (hTDP-WT-GFP) and human TDP-43 with a mutation in the nuclear localization sequence (hTDP-ΔNLS-GFP), to cause TDP-43 mislocalization, with ∼60% transduction efficiency achieved. Expression of both hTDP-WT-GFP and hTDP-ΔNLS-GFP resulted in changes to neurofilament expression, with cytoplasmic TDP-43 being associated with significantly (p<0.05) increased neurofilament heavy expression in the cell soma, and both forms of altered TDP-43 leading to significantly (p<0.05) decreased numbers of neurofilament-positive axons within the optic nerve. Alterations to neurofilament proteins were associated with significantly (p<0.05) increased microglial density in the optic nerve and retina. Furthermore expression of hTDP-WT-GFP was associated with a significant (p<0.05) increase in pre-synaptic input into RGCs in the retina. The current study has developed a new model allowing detailed examination of alterations to TDP-43 and will contribute to the knowledge of TDP-43-mediated neuronal alterations and degeneration.

中文翻译：

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TDP-43错位驱动神经丝变化的新型TDP-43蛋白病模型。

TAR DNA结合蛋白43（TDP-43）从细胞核到细胞质的定位错误是神经退行性疾病（如肌萎缩性侧索硬化症（ALS）和额颞叶变性（FTLD））的常见特征。体内下游这种错位的细胞效应尚不十分清楚。为了研究错位的TDP-43对神经元细胞体，轴突和轴突末端的影响，我们利用小鼠视觉系统创建了TDP-43蛋白病的新模型。小鼠（C57BL / 6J）视网膜神经节细胞（RGCs）转导有GFP标签的人野生型TDP-43（hTDP-WT-GFP）和人TDP-43，其核定位序列中有突变（hTDP-ΔNLS-GFP）导致TDP-43定位错误，转导效率约为60％。hTDP-WT-GFP和hTDP-ΔNLS-GFP的表达均导致神经丝表达的改变，细胞质中的TDP-43与细胞体中神经丝的大量表达显着相关（p <0.05），并且两种形式的TDP均发生改变-43导致显着（p <0。05）视神经内神经丝阳性轴突的数量减少。神经丝蛋白的改变与视神经和视网膜中的小胶质细胞密度显着增加（p <0.05）有关。此外，hTDP-WT-GFP的表达与视网膜中RGC的突触前输入显着增加（p <0.05）有关。当前的研究开发了一种新模型，可以详细检查TDP-43的改变，并将有助于了解TDP-43介导的神经元改变和变性。05）进入视网膜RGC的突触前输入增加。当前的研究开发了一种新模型，可以详细检查TDP-43的改变，并将有助于了解TDP-43介导的神经元改变和变性。05）进入视网膜RGC的突触前输入增加。当前的研究开发了一种新模型，可以详细检查TDP-43的改变，并将有助于了解TDP-43介导的神经元改变和变性。