To explore the molecular pathogenesis of
amyotrophic lateral sclerosis (ALS), the nuclear function of TAR-
DNA binding protein 43 kDa (TDP-43) must be elucidated. TDP-43 is a
nuclear protein that colocalizes with Cajal body or Gem in cultured cells. Several recent studies have reported that the decreasing number of Gems accompanied the depletion of the causative genes for ALS, TDP-43 and FUS. Gems play an important role in the pathogenesis of
spinal muscular atrophy. Gems are the sites of the maturation of spliceosomes, which are composed of uridylate-rich (U) snRNAs (small nuclear RNAs) and
protein complex, small nuclear ribonuclearprotein (
snRNP). Spliceosomes regulate the splicing of
pre-mRNA and are classified into the major or minor classes, according to the consensus sequence of acceptor and donor sites of
pre-mRNA splicing. Although the major class of spliceosomes regulates most
pre-mRNA splicing, minor spliceosomes also play an important role in regulating the splicing or global speed of
pre-mRNA processing. A mouse model of
spinal muscular atrophy, in which the number of Gems is decreased, shows fewer subsets U snRNAs. Interestingly, in the central nervous system, U snRNAs belonging to the minor spliceosomes are markedly reduced. In ALS, the
U12 snRNA is decreased only in the tissue affected by ALS and not in other tissues. Although the molecular mechanisms underlying the decreased
U12 snRNA resulting in cell dysfunction and cell death in
motor neuron diseases remain unclear, these findings suggest that the disturbance of nuclear bodies and minor splicing may underlie the common molecular pathogenesis of
motor neuron diseases.