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.
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Authors | Lien-Szu Wu, Wei-Cheng Cheng, C-K James Shen |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 287
Issue 33
Pg. 27335-44
(Aug 10 2012)
ISSN: 1083-351X [Electronic] United States |
PMID | 22718760
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- DNA-Binding Proteins
- Nerve Tissue Proteins
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Topics |
- Amyotrophic Lateral Sclerosis
(metabolism, pathology)
- Animals
- DNA-Binding Proteins
(biosynthesis, genetics)
- Female
- Gene Expression Regulation
- Gene Targeting
- Inclusion Bodies
(genetics, metabolism, pathology)
- Male
- Mice
- Mice, Knockout
- Motor Neurons
(metabolism, pathology)
- Nerve Tissue Proteins
(biosynthesis, genetics)
- Phenotype
- Spinal Cord
(metabolism, pathology)
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