, 2009; Li et al., 2010), but which is

unlikely to be a model for nuclear depletion through cytoplasmic sequestration. The essential role of TDP-43 for early embryonic development in mammals has recently been shown using an elegant gene-trap approach, demonstrating early lethality of TARDBP-knockout mice (Sephton et al., 2010). TDP-43 is a developmentally regulated protein essential for early embryonic development. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis (Kraemer et al., 2010). Interestingly, the heterozygous knockout mice (TARDBP+/−) showed signs of motor dysfunction, although no abnormalities in their motor neurons were apparent. Overexpression Selleckchem Regorafenib of mutant TDP-43A315T driven by the prion promoter in mouse yielded expression of the transgene in neurons and glial cells throughout the nervous system and resulted in degeneration of motor neurons and of layer V cortical neurons (Wegorzewska et al., 2009). Expression of the TDP-43A315T was about three-fold that of endogenous TDP-43. These mice developed a paralyzing disease characterised by loss of upper

Thiazovivin and lower motor neurons. Interestingly, degenerating neurons contained ubiquitinated aggregates which, in spite of thorough investigation, did not contain the mutant TDP-43A315T. Loss of TDP-43 immunoreactivity from the nucleus was seen occasionally but did not seem to be a prominent finding. On the other hand, 25-kDa fragments appeared early in the disease. Unfortunately, this study did not report the findings in wildtype TDP-43-overexpressing mice. Not surprisingly, based on the effects seen in other models such as Drosophila (Feiguin et al., 2009; Li et al., 2010), overexpression of human wildtype TDP-43 driven by the Thy1 promotor in mice gave rise to a phenotype Acyl CoA dehydrogenase as well. This promoter results in postnatal neuronal expression of the transgene. Expression of wildtype TDP-43 to a degree similar to that of TDP-43A315T in the previous study resulted in no phenotype. When increasing the level of wildtype TDP-43 expression, animals developed gait abnormalities and showed evidence for degeneration

of motor neurons and neurons in layer V of the frontal cortex (Wils et al., 2010). The severity of the phenotype was parallel to the degree of TDP-43wt expression. In the diseased neurons, nuclear and cytoplasmic aggregates of ubiquitinated and phosphorylated TDP-43 were found. In this study, C-terminal 25-kDa fragments were found in the nuclear fraction. In this report, no TDP-43mutant was overexpressed. It is difficult to compare these two models. Overexpression of TDP-43 seems to be toxic and may switch TDP-43 into TDP-43SALS/FTLD. The presence of a mutation favours this switch, although it needs to be taken into account that, in the TDP-43mutant study, glial cells also expressed the transgene and this may contribute to the process of neuronal degeneration, as we have learnt from the SOD1 model.