Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS
Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS
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DOI：
10.1007/s00401-015-1486-0
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发表时间：
2015-11-01
影响因子：
12.7
通讯作者：
Ittner, Lars M.
中科院分区：
文献类型：
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作者：
Ke, Yazi D.;van Hummel, Annika;Ittner, Lars M.
在肌萎缩性侧索硬化症（ALS）和额颞叶变性（FTLD）中，核交换反应dna结合蛋白43 （TDP-43）在神经元胞浆沉积形成的过程中重新定位到细胞质。在家族性ALS和非突变的人类TDP-43中，编码TARDBP基因的TDP-43致病性突变已被用于在细胞培养和动物（包括小鼠）中模拟FTD/ALS。在这里，我们报道了一种新的A315T突变TDP-43转基因小鼠，iTDP-43 (A315T)，具有控制神经元过表达。人类TDP-43 （A315T）的组成性表达导致明显的早发性和进行性神经变性，这与运动能力、空间记忆和去抑制功能受损有关。肌肉萎缩导致握力下降。皮层变性表现为明显的星形胶质细胞活化。利用从iTDP-43 （A315T）脑中提取的差异蛋白，我们发现了TDP-43的细胞质定位、断裂、磷酸化和泛素化以及不溶性。令人惊讶的是，在明显神经退行性变小鼠中抑制人TDP-43 （A315T）表达仅1周就足以显著改善运动和行为缺陷，并减少星形胶质细胞增生。我们的数据表明，iTDP-43 （A315T）小鼠的功能缺陷至少部分是TDP-43 （A315T）存在的直接和短暂影响。此外，它说明了一旦转基因TDP-43被移除受损神经元的代偿能力，这对未来的治疗有意义。
The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43 (A315T) , with controlled neuronal over-expression. Constitutive expression of human TDP-43 (A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43 (A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43 (A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43 (A315T) mice are at least in part a direct and transient effect of the presence of TDP-43 (A315T) . Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.