ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snrnps核糖核蛋白装配缺陷与脊髓性肌萎缩的严重程度和优先影响的一个子集spliceosomal snrnps.pdfVIP

Ribonucleoprotein Assembly Defects Correlate with Spinal Muscular Atrophy Severity and Preferentially Affect a Subset of Spliceosomal snRNPs 1 2 1,3 1 2 1,3 Francesca Gabanella , Matthew E. R. Butchbach , Luciano Saieva , Claudia Carissimi , Arthur H. M. Burghes , Livio Pellizzoni * 1 Dulbecco Telethon Institute, Institute of Cell Biology, Monterotondo Scalo, Rome, Italy, 2 Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio, United States of America, 3 Center for Motor Neuron Biology and Disease, Department of Pathology, Columbia University Medical Center, New York, New York, United States of America Spinal muscular atrophy (SMA) is a motor neuron disease caused by reduced levels of the survival motor neuron (SMN) protein. SMN together with Gemins2-8 and unrip proteins form a macromolecular complex that functions in the assembly of small nuclear ribonucleoproteins (snRNPs) of both the major and the minor splicing pathways. It is not known whether the levels of spliceosomal snRNPs are decreased in SMA. Here we analyzed the consequence of SMN deficiency on snRNP metabolism in the spinal cord of mouse models of SMA with differing phenotypic severities. We demonstrate that the expression of a subset of Gemin proteins and snRNP assembly activity are dramatically reduced in the spinal cord of severe SMA mice. Comparative analysis of different tissues highlights a similar decrease in SMN levels and a strong impairment of snRNP assembly in tissues of severe SMA mice, although the defect appears smaller in kidney than in neural tissue. We further show that the extent of reduction in both Gemin proteins expression and snRNP assembly activity in the spinal cord of SMA mice correlates with disease severity. Remarkably, defec