Synaptic protein dysregulation in myotonic dystrophy type 1 Disease neuropathogenesis beyond missplicing
Synaptic protein dysregulation in myotonic dystrophy type 1 Disease neuropathogenesis beyond missplicing
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DOI：
10.4161/rdis.25553
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发表时间：
2013-01-01
期刊：
影响因子：
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通讯作者：
Gomes-Pereira, Mario
中科院分区：
文献类型：
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作者：
Hernandez-Hernandez, Oscar;Sicot, Geraldine;Gomes-Pereira, Mario
在1型肌强直性营养不良（DM1）中，扩增转录本的毒性主要是由选择性剪接的破坏介导的。然而，中枢神经系统（CNS）的详细发病机制尚未完全阐明。在我们最近的研究中，我们证明了DM1小鼠模型的中枢神经系统中突变转录物的积累以区域特异性的方式干扰剪接。我们现在讨论剪接因子的时空调控表达可能有助于DM1脑的区域特异性剪接病。在寻找中枢神经系统疾病机制的过程中，我们发现含有cug的扩增RNA的表达影响突触囊泡蛋白的表达和磷酸化，可能导致DM1神经表型。尽管剪接调节因子介导了DM1的作用，但突触蛋白的错误调节与它们的编码转录物的错误剪接无关，这支持了DM1在中枢神经系统中的机制除了剪接程序的中断外还具有深远影响的观点。
The toxicity of expanded transcripts in myotonic dystrophy type 1 ( DM1) is mainly mediated by the disruption of alternative splicing. However, the detailed disease mechanisms in the central nervous system (CNS) have not been fully elucidated. In our recent study, we demonstrated that the accumulation of mutant transcripts in the CNS of a mouse model of DM1 disturbs splicing in a region-specific manner. We now discuss that the spatial-and temporalregulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains. In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes. Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program.