Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
Acta Neuropathol. 2010 Apr;119(4):409-19. doi: 10.1007/s00401-010-0659-0. Epub 2010 Mar 3.
Abnormal TDP-43 aggregation is a prominent feature in the neuropathology of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Mutations in TARDBP, the gene encoding TDP-43, cause some cases of ALS. The normal function of TDP-43 remains incompletely understood. To better understand TDP-43 biology, we generated mutant mice carrying a genetrap disruption of Tardbp. Mice homozygous for loss of TDP-43 are not viable. TDP-43 deficient embryos die about day 7.5 of embryonic development thereby demonstrating that TDP-43 protein is essential for normal prenatal development and survival. However, heterozygous Tardbp mutant mice exhibit signs of motor disturbance and muscle weakness. Compared with wild type control littermates, Tardbp (+/-) animals have significantly decreased forelimb grip strength and display deficits in a standard inverted grid test despite no evidence of pathologic changes in motor neurons. Thus, TDP-43 is essential for viability, and mild reduction in TDP-43 function is sufficient to cause motor deficits without degeneration of motor neurons.
TDP-43 异常聚集是肌萎缩侧索硬化症（ALS）和额颞叶变性神经病理学的一个突出特征。编码 TDP-43 的 TARDBP 基因突变导致一些 ALS 病例。TDP-43 的正常功能仍不完全清楚。为了更好地了解 TDP-43 的生物学特性，我们生成了携带 Tardbp 基因陷阱破坏的突变小鼠。TDP-43 纯合缺失的小鼠不能存活。TDP-43 缺失的胚胎在胚胎发育约第 7.5 天死亡，从而表明 TDP-43 蛋白对于正常的产前发育和存活是必需的。然而，杂合 Tardbp 突变小鼠表现出运动障碍和肌肉无力的迹象。与野生型对照同窝仔相比，Tardbp（ +/-）动物的前肢握力明显降低，并且在标准倒置网格测试中表现出缺陷，尽管运动神经元没有病理变化的证据。因此，TDP-43 对于存活是必需的，并且 TDP-43 功能的轻度降低足以导致运动缺陷而不会导致运动神经元退化。
