Erschienen in:
01.04.2010 | Original Paper
Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis
verfasst von:
Brian C. Kraemer, Theresa Schuck, Jeanna M. Wheeler, Linda C. Robinson, John Q. Trojanowski, Virginia M. Y. Lee, Gerard D. Schellenberg
Erschienen in:
Acta Neuropathologica
|
Ausgabe 4/2010
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Abstract
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.