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.
Highlights
Most amyotrophic lateral sclerosis (ALS) cases are characterized with TDP-43(ϩ), ubiquitin(ϩ) inclusions in their diseased spinal cord motor neurons
The results described above altogether indicated that the spinal cords, in particular the ventral horn of the lumbar spinal cord, of mutant HB9:Cre-Tardbplx/Ϫ mice underwent significant motor neuron loss, reactive astrocytosis, microglia activation, and accumulation of polyubiquitinated proteins, all of which were characteristic of ALS with TDP-43(ϩ) ubiquitinpositive inclusions (UBIs)
Because these HB9:Cre-Tardbplx/Ϫ mice are the first mouse model with targeted depletion of TDP-43 expression in the spinal cord motor neurons and 90% of the non-SOD1, non-FUSinclusion type ALS patients are signatures with TDP-43(ϩ) UBIs, this mouse model we have generated should be valuable for research of ALS with TDP-43 proteinopathies
Summary
Most amyotrophic lateral sclerosis (ALS) cases are characterized with TDP-43(ϩ), ubiquitin(ϩ) 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. This study establishes an important role of TDP-43 in the long term survival and functioning of the mammalian spinal cord motor neurons, and establishes that loss of TDP-43 function could be one major cause for neurodegeneration in ALS with TDP-43 proteinopathies. As described in the following, we have taken advantage of the Tardbplx mouse line from that study and generated mice with spinal cord motor neuron-specific knock-out of TDP-43 expression. These mice exhibit pathological phenotypes in striking similarity to ALS
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