C9ORF72 and the 43 kDa TAR DNA-binding protein (TDP-43) are key molecules in the development of TDP-43 pathology in amyotrophic lateral sclerosis (ALS). Accumulating evidence indicate that both molecules tightly associate with RNA metabolism, indicating that the RNA is a target for therapeutic strategy for ALS. To elucidate the precious target in ALS, we have to elucidate the molecular mechanism of ALS associated with these molecules in detail. In my talk, I would like to focus on the three issues on RNA metabolism regarding TDP-43. For the disease initiation, it has been speculated that the misregulation of the amounts of TDP-43 may trigger the abnormal dislocation of TDP-43. One of the important functions of TDP-43 is an autoregulation of its own amounts of mRNA. I would like to introduce the fine mechanism of the regulation of the amounts of TDP-43. Next, regarding the normal function of TDP-43 in nucleus, we have found that TDP-43 associate with the RNA metabolism. TDP-43 associates with nuclear bodies including Gemini of coiled bodies (GEMs). GEMs decreased in both TDP-43-depleted HeLa cells and spinal motor neurons in ALS patients. GEMs contribute to the biogenesis of uridine-rich small nuclear RNA (U snRNA), a component of a splicing machinery. Levels of several U snRNAs decreased in TDP-43-depleted SH-SY5Y and U87MG cells. The level of U12 snRNA was decreased in tissues affected by ALS. Immunohistochemical analysis revealed the decrease of U11/12-type small nuclear ribonucleoproteins in spinal motor neurons of ALS patients. These findings suggest that a loss of TDP-43 function decrease the number of GEMs, which is followed by a disturbance of pre-mRNA splicing by the U11/U12 spliceosome in tissues affected by ALS. The number of GEMs and a subset of U snRNAs also decrease in spinal muscular atrophy, lower motor neuron disease. The similarity suggests that an alteration of U snRNAs also underlie the molecular pathogenesis of ALS. The TDP-43 mRNA regulation or the improvement of the altered splicing of some specific gene could be a new therapeutic strategy for ALS.