Identification and Characterisation of Simiate, a Novel Protein Linked to the Fragile X Syndrome
Identification and Characterisation of Simiate, a Novel Protein Linked to the Fragile X Syndrome
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DOI：
10.1371/journal.pone.0083007
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发表时间：
2013-12-11
期刊：
影响因子：
3.7
通讯作者：
Dahlhaus, Regina
中科院分区：
文献类型：
--
作者：
Derlig, Kristin;Giessl, Andreas;Dahlhaus, Regina
在发育阶段和对环境信号的反应中，对蛋白质表达的严格调控对每个细胞和生物体都是必不可少的。最近的研究表明，哺乳动物的大脑对特定蛋白质表达模式的变化特别敏感，认知缺陷以及自闭症行为与蛋白质表达失调有关。一种以多种蛋白质表达变化为特征的智力障碍是脆性X综合征。由于缺失了一种单一的mRNA结合蛋白，即脆性X智力低下蛋白FMRP，该病发生了巨大的mRNA代谢失调。在这里，我们介绍了一种名为Simiate的新蛋白的鉴定和性质，它的mRNA包含几个FMRP识别基序，并在共沉淀时与FMRP结合。序列分析表明，该蛋白进化了APP。17亿年前真核生物发展的时候。应用针对Simiate产生的抗体，在包括哺乳动物大脑在内的各种组织中检测到这种蛋白质。在亚细胞水平上，Simiate定位于体细胞和核斑点。我们发现，在FMR1(-/-)小鼠中，Simiate和核斑点经历了特定的变化。一种基于抗体的内源性Simiate阻断揭示了这种蛋白质对细胞生存是必不可少的。这些发现不仅表明Simiate在基因转录和/或RNA剪接中发挥了重要作用，而且也为核斑点在脆性X综合征中的作用提供了证据。事实上，转录和剪接是控制蛋白质表达的两个基本机制，不仅是突触可塑性和记忆形成的基础，而且在一些与精神残疾相关的疾病中也受到影响。
A strict regulation of protein expression during developmental stages and in response to environmental signals is essential to every cell and organism. Recent research has shown that the mammalian brain is particularly sensitive to alterations in expression patterns of specific proteins and cognitive deficits as well as autistic behaviours have been linked to dysregulated protein expression. An intellectual disability characterised by changes in the expression of a variety of proteins is the fragile X syndrome. Due to the loss of a single mRNA binding protein, the Fragile X Mental Retardation Protein FMRP, vast misregulation of the mRNA metabolism is taking place in the disease. Here, we present the identification and characterisation of a novel protein named Simiate, whose mRNA contains several FMRP recognition motifs and associates with FMRP upon co-precipitation. Sequence analysis revealed that the protein evolved app. 1.7 billion years ago when eukaryotes developed. Applying antibodies generated against Simiate, the protein is detected in a variety of tissues, including the mammalian brain. On the subcellular level, Simiate localises to somata and nuclear speckles. We show that Simiate and nuclear speckles experience specific alterations in FMR1(-/-) mice. An antibody-based block of endogenous Simiate revealed that the protein is essential for cell survival. These findings suggest not only an important role for Simiate in gene transcription and/or RNA splicing, but also provide evidence for a function of nuclear speckles in the fragile X syndrome. Indeed, transcription and splicing are two fundamental mechanisms to control protein expression, that underlie not only synaptic plasticity and memory formation, but are also affected in several diseases associated with mental disabilities.