Revealing protein synthesis defects in Fragile X Syndrome with new chemical tools

描述（申请人提供）：脆性X综合征是自闭症最常见的遗传原因，每6000名新生儿中就有1名发生。受影响的患者还患有智力迟钝，在某些情况下还患有癫痫。目前的治疗方法包括使用药物来改善情绪和注意力症状并预防癫痫发作，但无法恢复正常的学习和情绪功能。从分子水平上了解脆性X综合征的神经元缺陷对于合理设计治疗方案以解决疾病的根本原因是必要的。在这种疾病中突变的蛋白质，即脆性X智力低下蛋白（FMRP），是调节激活的突触（神经元之间的通讯点）的蛋白质合成所必需的。大量的证据表明，作为学习基础的突触的正常加强和减弱需要通过突触活动对蛋白质合成进行仔细的调节。实验还表明FMRP在调节突触加强和减弱中的作用。然而，突触强化和弱化、蛋白质合成和FMRP之间的精确关系知之甚少。例如，哪些蛋白质是在突触强化和弱化期间合成的，用于突触强化和弱化，或者突触强化和弱化需要哪些蛋白质，以及这些事件中的哪些事件受到FMRP丢失的影响，这些都是未知的。FMRP在活性依赖性局部蛋白质合成中的功能的研究受到用于评估和控制活神经元中蛋白质合成的方法的低灵敏度和分辨率的限制。我们已经开发了新的分子工具，允许实时跟踪和控制新的蛋白质合成和可视化的激酶途径参与活性诱导的蛋白质合成。我们建议使用这些工具来检查特异性的蛋白质合成反应在突触加强与减弱，并研究FMRP损失对这些反应的影响。我们还将确定哪些新蛋白质通常是持久的突触可塑性所需的，以及FMRP丢失如何改变这些要求。这些研究将深入了解突触蛋白合成在持续突触可塑性中的调节和功能，确定治疗干预的潜在分子靶点，并产生可使更大的神经科学界受益的新技术。 公共卫生相关性：脆性X综合征是自闭症和精神发育迟滞最常见的遗传原因，目前对脆性X综合征的治疗在改善精神和神经功能方面仅部分有效。我们的建议将应用新的分子工具来揭示脆性X综合征的学习和情绪症状的分子基础。这些知识将有助于确定治疗脆性X综合征和其他自闭症谱系疾病的药物开发的可能目标。

DESCRIPTION (provided by applicant): Fragile X syndrome is the most common genetic cause of autism, occurring in 1 out of 6000 births. Affected patients also suffer from mental retardation and in some cases seizures. Current treatments involve the use of drugs to ameliorate mood and attention symptoms and to prevent seizures, but are not able to restore normal learning and emotional function. A molecular-level understanding of the neuronal defects in Fragile X syndrome will be necessary for the rational design of therapies to address the underlying cause of the disease. The protein mutated in the disease, the Fragile X mental retardation protein (FMRP), is required for regulating protein synthesis at activated synapses, the communication points between neurons. A large body of evidence suggests that the normal strengthening and weakening of synapses that underlies learning requires the careful regulation of protein synthesis by synaptic activity. Experiments have also suggested a role for FMRP in regulating both synaptic strengthening and weakening. However, the precise relationship between synaptic strengthening and weakening, protein synthesis, and FMRP is poorly understood. For instance, which proteins are synthesized during, utilized in, or required for synaptic strengthening and weakening, and which of these events are affected by FMRP loss, is not known. Research on the function of FMRP in activity-dependent local protein synthesis has been limited by the low sensitivity and resolution of methods for assessing and controlling protein synthesis in living neurons. We have developed new molecular tools that allow the real-time tracking and control of new protein synthesis and the visualization of kinase pathways involved in activity-induced protein synthesis. We propose to use these tools to examine the specificity of protein synthesis responses in synaptic strengthening versus weakening, and to study the effect of FMRP loss on these responses. We will also determine which new proteins are normally required for long-lasting synaptic plasticity, and how FMRP loss might alter those requirements. These studies will provide insight into the regulation and function of synaptic protein synthesis in persistent synaptic plasticity, identify potential molecular targets for therapeutic intervention, and produce new technologies that can benefit the larger neuroscience community. PUBLIC HEALTH RELEVANCE: Current treatments for Fragile X syndrome, the most common genetic cause of autism and mental retardation, are only partially effective in improving mental and neurological function. Our proposal will apply new molecular tools to reveal the molecular bases of the learning and emotional symptoms in Fragile X syndrome. This knowledge will be useful in identifying possible targets for the development of drugs to treat Fragile X syndrome and potentially other autism spectrum diseases.