Targeted Depletion of TDP-43 Expression in the Spinal Cord Motor Neurons Leads to the Development of Amyotrophic Lateral Sclerosis-like Phenotypes in Mice

• Published in: The Journal of biological chemistry 2012-08, Vol.287 (33), p.27335-27344
• Main Authors: Wu, Lien-Szu, Cheng, Wei-Cheng, Shen, C.-K. James
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Amyotropic Lateral Sclerosis (Lou Gehrig's Disease); Animals; Cell Death; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Female; Gene Expression Regulation; Gene Targeting; Inclusion Bodies - genetics; Inclusion Bodies - metabolism; Inclusion Bodies - pathology; Male; Mice; Mice, Knockout; Molecular Bases of Disease; Motor Dysfunction; Motor Neuron Loss; Motor Neurons - metabolism; Motor Neurons - pathology; Mouse Genetics; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Neurodegenerative Diseases; Phenotype; RNA-binding Proteins; Spinal Cord - metabolism; Spinal Cord - pathology; Targeted Gene Knock-out In Mice; TDP-43
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.359000

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-Tardbplx/−) 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–Tardbplx/− 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. Background: Most amyotrophic lateral sclerosis (ALS) cases are characterized with TDP-43(+), ubiquitin(+) inclusions in their diseased spinal cord motor neurons. Results: Mice with targeted depletion of TDP-43 expression in the spinal cord motor neurons developed a range of ALS-like phenotypes. Conclusion: TDP-43 is essential for the survival and functioning of mammalian spinal cord motor neurons. Significance: Loss of TDP-43 function could be one major cause for neurodegeneration in ALS with TDP-43 proteinopathies.