Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice

Lien Szu Wu, Wei Cheng Cheng, C. K.James Shen

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

ALS, or amyotrophic lateral sclerosis, is a progressive and fatal motor neuron disease with no effective medicine. Importantly, the majority of the ALS cases are with TDP-43 proteinopathies characterized with TDP-43-positive, ubiquitin-positive inclusions (UBIs) in the cytosol. However, the role of the mismetabolism of TDP-43 in the pathogenesis of ALS with TDP-43 proteinopathies is unclear. Using the conditional mouse gene targeting approach, we show that mice with inactivation of the Tardbp gene in the spinal cord motor neurons (HB9:Cre-Tardbp lx/-) exhibit progressive and male-dominant development of ALS-related phenotypes including kyphosis, motor dysfunctions, muscle weakness/atrophy, motor neuron loss, and astrocytosis in the spinal cord. Significantly, ubiquitinated proteins accumulate in the TDP-43-depleted motor neurons of the spinal cords of HB9:Cre-Tardbp lx/- mice with the ALS phenotypes. This study not only establishes an important role of TDP-43 in the long term survival and functioning of the mammalian spinal cord motor neurons, but also establishes that loss of TDP-43 function could be one major cause for neurodegeneration in ALS with TDP-43 proteinopathies.

Original languageEnglish
Pages (from-to)27335-27344
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number33
DOIs
Publication statusPublished - Aug 10 2012
Externally publishedYes

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TDP-43 Proteinopathies
Amyotrophic Lateral Sclerosis
Motor Neurons
Neurons
Spinal Cord
Phenotype
Ubiquitinated Proteins
Motor Neuron Disease
Kyphosis
Gliosis
Muscular Atrophy
Gene Targeting
Muscle Weakness
Gene Silencing
Ubiquitin
Genes
Cytosol
Medicine
Muscle

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. / Wu, Lien Szu; Cheng, Wei Cheng; Shen, C. K.James.

In: Journal of Biological Chemistry, Vol. 287, No. 33, 10.08.2012, p. 27335-27344.

Research output: Contribution to journalArticle

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