Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis.

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TitleLoss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis.
Publication TypeJournal Article
Year of Publication2010
AuthorsKraemer BC, Schuck T, Wheeler JM, Robinson LC, Trojanowski JQ, M Y Lee V, Schellenberg GD
JournalActa Neuropathol
Volume119
Issue4
Pagination409-19
Date Published2010 Apr
ISSN1432-0533
KeywordsAmyotrophic Lateral Sclerosis, Animals, DNA-Binding Proteins, Embryonic Development, Forelimb, Hand Strength, Heterozygote, Mice, Mice, Inbred C57BL, Motor Activity, Motor Neurons, Muscle, Skeletal, Mutation
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.
DOI10.1007/s00401-010-0659-0
Alternate JournalActa Neuropathol.
PubMed ID20198480
PubMed Central IDPMC2880609
Grant ListP01 AG017586 / AG / NIA NIH HHS / United States
R01 NS064131 / NS / NINDS NIH HHS / United States
AG17586 / AG / NIA NIH HHS / United States
R01 NS064131-01A1 / NS / NINDS NIH HHS / United States
NS064131 / NS / NINDS NIH HHS / United States