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Title | Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Kraemer BC, Schuck T, Wheeler JM, Robinson LC, Trojanowski JQ, M Y Lee V, Schellenberg GD |
Journal | Acta Neuropathol |
Volume | 119 |
Issue | 4 |
Pagination | 409-19 |
Date Published | 2010 Apr |
ISSN | 1432-0533 |
Keywords | Amyotrophic 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. |
DOI | 10.1007/s00401-010-0659-0 |
Alternate Journal | Acta Neuropathol. |
PubMed ID | 20198480 |
PubMed Central ID | PMC2880609 |
Grant List | P01 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 |