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

Institute of Molecular Biology, Academia Sinica, Taipei 11574, Taiwan.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2012; 287(33):27335-44. DOI: 10.1074/jbc.M112.359000
Source: PubMed


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.

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    • "In some cases (those related to a loss-of-function of the mutated protein, e.g., TDP- 43), knockout models have been also developed for the study of motor neuron injury (Wu et al., 2012). As mentioned above, these models have facilitated studies addressed to identify the key events in ALS pathogenesis that are more directly related to the specific gene used for modeling, but they have also served for evaluating numerous neuroprotective compounds or other disease-modifying strategies. "
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    • "Lipocalin-2 is a feature of inflammatory astrocytes (Zamanian et al., 2012) and can enhance reactive astrogliosis via autocrine signaling (Lee et al., 2009). Specific knockout of TDP-43 in cortical and MNs in mice produced a less severe phenotype, which further highlights the contribution of multiple cell types in ALS and FTD (Wu et al., 2012b; Iguchi et al., 2013). Interestingly, overexpression of ALS associated mutant TDP-43 driven by an astrocytic promoter was sufficient to cause MN degeneration in rats and was also associated with marked up-regulation of lipocalin-2 in reactive astrocytes (Tong et al., 2013). "
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    • "These findings, coupled with the observation that many TDP-43 mutations occur around the prion-like motif, suggest that ALS and FTLD-TDP may be caused by aggregation of TDP-43 which inhibits its normal cellular activities. This loss of TDP-43 function may ultimately be instrumental in disease pathogenesis, and additionally the TDP-43 aggregates may sequester other essential RNAs and proteins [15]. Furthermore, the tremendous variety of reported TDP-43 inclusions suggests distinct mechanisms that may result from the misregulation of disease-specific and potentially overlapping signaling pathways that ultimately lead to TDP-43 accumulation and the subsequent functional deficits characteristic of all diseases with TDP-43 inclusions [16], [17]. "
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