TAR-DNA-binding protein 43 kDa (TDP-43) is a major component protein of ubiquitin-positive inclusions in brains of patients with amyotrophic lateral sclerosis (ALS). Disappearance of TDP-43 from the nucleus is the histopathological hallmark of ALS. In addition, mutation of TDP-43 is linked to ALS. TDP-43 can autoregulate its own expression and it has been proposed that disturbance in the autoregulation may underlie the pathogenesis of ALS. However, the autoregulatory mechanism and its relationship to this illness have not been fully elucidated.
We found that a selection of polyadenylation sites and regulation of the intracellular distribution of the TDP-43 mRNA participate in the TDP-43 autoregulation mechanism. Therefore, we investigate the intracellular distribution of TDP-43 mRNA in the affected spinal motor neuron with ALS. We compared the proportions of TDP-43 mRNA in the nucleus per cell between ALS and control subjects in spinal motor neuron by in situ hybridization using QuantiGene ViewRNATM. We found that the proportion of the number of the dots in the nucleus is significantly decreased in ALS than in control. We subsequently compared the proportions of TDP-43 mRNA in the nucleus with or without nuclear TDP-43 protein by immunostaining of serial sections. The ratio of the number of the dots in the nucleus with TDP-43 protein was significantly lower than that of cells with nuclear TDP-43, which implied an increase in translatable cytoplasmic mRNA. These results indicate that the autoregulatory machinery of TDP-43 mRNA was preserved in the affected motor neuron with ALS. The continuous stimulation of the TDP-43 production due to depletion of nuclear TDP-43 may facilitate the inclusion formation of TDP-43.