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首页> 外文期刊>PLoS Genetics >Alternative Splicing Events Are a Late Feature of Pathology in a Mouse Model of Spinal Muscular Atrophy
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Alternative Splicing Events Are a Late Feature of Pathology in a Mouse Model of Spinal Muscular Atrophy

机译：替代剪接事件是脊髓性肌萎缩症小鼠模型中病理的晚期特征。

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Spinal muscular atrophy is a severe motor neuron disease caused by inactivating mutations in the SMN1 gene leading to reduced levels of full-length functional SMN protein. SMN is a critical mediator of spliceosomal protein assembly, and complete loss or drastic reduction in protein leads to loss of cell viability. However, the reason for selective motor neuron degeneration when SMN is reduced to levels which are tolerated by all other cell types is not currently understood. Widespread splicing abnormalities have recently been reported at end-stage in a mouse model of SMA, leading to the proposition that disruption of efficient splicing is the primary mechanism of motor neuron death. However, it remains unclear whether splicing abnormalities are present during early stages of the disease, which would be a requirement for a direct role in disease pathogenesis. We performed exon-array analysis of RNA from SMN deficient mouse spinal cord at 3 time points, pre-symptomatic (P1), early symptomatic (P7), and late-symptomatic (P13). Compared to littermate control mice, SMA mice showed a time-dependent increase in the number of exons showing differential expression, with minimal differences between genotypes at P1 and P7, but substantial variation in late-symptomatic (P13) mice. Gene ontology analysis revealed differences in pathways associated with neuronal development as well as cellular injury. Validation of selected targets by RT–PCR confirmed the array findings and was in keeping with a shift between physiologically occurring mRNA isoforms. We conclude that the majority of splicing changes occur late in SMA and may represent a secondary effect of cell injury, though we cannot rule out significant early changes in a small number of transcripts crucial to motor neuron survival.
机译：脊髓性肌萎缩是一种严重的运动神经元疾病，由SMN1基因的失活引起，导致全长功能性SMN蛋白水平降低。 SMN是剪接体蛋白装配的关键介体，蛋白的完全丧失或急剧减少会导致细胞活力丧失。但是，目前尚不了解当SMN降低到所有其他细胞类型都能耐受的水平时选择性运动神经元退化的原因。最近在SMA小鼠模型的末期报道了广泛的剪接异常，导致提出这样的主张，即有效剪接的破坏是运动神经元死亡的主要机制。但是，尚不清楚在疾病的早期阶段是否存在剪接异常，这可能是在疾病发病机理中发挥直接作用的必要条件。我们在3个时间点（症状发作前（P1），早期症状发作（P7）和症状晚期（P13））对来自SMN缺陷小鼠脊髓的RNA进行了外显子阵列分析。与同窝对照小鼠相比，SMA小鼠显示出随时间变化的外显子数量，这些外显子具有差异表达，P1和P7基因型之间的差异极小，而症状晚期（P13）小鼠则有很大差异。基因本体分析揭示了与神经元发育以及细胞损伤相关的途径的差异。通过RT-PCR对选定靶标的验证证实了该阵列的发现，并且与生理发生的mRNA同工型之间的变化保持一致。我们得出的结论是，大多数剪接变化发生在SMA晚期，可能代表了细胞损伤的继发效应，尽管我们不能排除少数对运动神经元存活至关重要的转录本的显着早期变化。

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