Pellizzoni L, Kataoka N, Charroux B, Dreyfuss G
Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia 19104-6148, USA.
Cell. 1998 Nov 25;95(5):615-24. doi: 10.1016/s0092-8674(00)81632-3.
Spinal muscular atrophy (SMA) is a common motor neuron degenerative disease that results from reduced levels of, or mutations in, the Survival of Motor Neurons (SMN) protein. SMN is found in the cytoplasm and the nucleus where it is concentrated in gems. SMN interacts with spliceosomal snRNP proteins and is critical for snRNP assembly in the cytoplasm. We show that a dominant-negative mutant SMN (SMNdeltaN27) causes a dramatic reorganization of snRNPs in the nucleus. Furthermore, SMNdeltaN27 inhibits pre-mRNA splicing in vitro, while wild-type SMN stimulates splicing. SMN mutants found in SMA patients cannot stimulate splicing. These findings demonstrate that SMN plays a crucial role in the generation of the pre-mRNA splicing machinery and thus in mRNA biogenesis, and they link the function of SMN in this pathway to SMA.
脊髓性肌萎缩症（SMA）是一种常见的运动神经元退行性疾病，由运动神经元存活蛋白（SMN）水平降低或发生突变所致。SMN存在于细胞质和细胞核中，在核宝石中高度富集。SMN与剪接体snRNP蛋白相互作用，对细胞质中snRNP的组装至关重要。我们发现，显性负性突变体SMN（SMNdeltaN27）会导致细胞核中snRNPs发生显著重组。此外，SMNdeltaN27在体外抑制前体mRNA剪接，而野生型SMN则刺激剪接。在SMA患者中发现的SMN突变体无法刺激剪接。这些发现表明，SMN在生成前体mRNA剪接机制以及mRNA生物合成过程中发挥着关键作用，并且将SMN在该途径中的功能与SMA联系起来。
