Department of Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata, Japan.
Neuropathology. 2014 Feb;34(1):99-107. doi: 10.1111/neup.12070. Epub 2013 Sep 22.
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.
为了探索肌萎缩侧索硬化症（ALS）的分子发病机制，必须阐明 TAR-DNA 结合蛋白 43kDa（TDP-43）的核功能。TDP-43 是一种核蛋白，在培养细胞中与 Cajal 体或 Gem 共定位。最近的几项研究报告称，随着 ALS 的致病基因 TDP-43 和 FUS 的耗竭，Gem 的数量减少。Gem 在脊髓性肌萎缩症的发病机制中起重要作用。Gem 是剪接体成熟的部位，剪接体由富含尿嘧啶（U）的 snRNA（小核 RNA）和蛋白质复合物小核核糖核蛋白（snRNP）组成。剪接体调节前体 mRNA 的剪接，并根据前体 mRNA 剪接的接受和供体位点的一致序列分为主要或次要类别。虽然主要类别的剪接体调节大多数前体 mRNA 的剪接，但次要剪接体也在调节前体 mRNA 加工的剪接或整体速度方面发挥重要作用。Gem 数量减少的脊髓性肌萎缩症小鼠模型显示出更少的 U snRNA 亚群。有趣的是，在中枢神经系统中，属于次要剪接体的 U snRNA 明显减少。在 ALS 中，仅在受 ALS 影响的组织中而非其他组织中减少 U12 snRNA。尽管导致运动神经元疾病中细胞功能障碍和细胞死亡的 U12 snRNA 减少的分子机制尚不清楚，但这些发现表明核体和次要剪接的紊乱可能是运动神经元疾病共同的分子发病机制的基础。
