Imbalance of synaptic actin dynamics as a key to fragile X syndrome?
Imbalance of synaptic actin dynamics as a key to fragile X syndrome?
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DOI：
10.1113/jp275571
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发表时间：
2018-07-15
影响因子：
5.5
通讯作者：
Korte, Martin
中科院分区：
文献类型：
--
作者：
Michaelsen-Preusse, Kristin;Feuge, Jonas;Korte, Martin
我们的经历和记忆决定了我们是谁，越来越多的证据表明，记忆的形成依赖于我们大脑中突触结构的功能和结构适应。尤其是树突棘，突触的突触后间隔表现出很强的结构-功能关系和高度的结构可塑性。虽然分子机制还不完全清楚，但已知这些修饰高度依赖于肌动蛋白细胞骨架，它是脊柱的主要细胞骨架成分。鉴于肌动蛋白在这些机制中的关键作用，从精神分裂症到几种形式的自闭症谱系障碍，如脆性X综合征(FXS)，都可以在各种神经疾病中发现脊柱肌动蛋白动力学的失调(反映在树突棘突的改变上)。FXS是由单个突变导致X连锁的脆性X智力低下1基因失活及其基因产物--RNA结合蛋白脆性X智力低下蛋白1(FMRP)引起的，FMRP通常在突触前和突触后都可以发现。FMRP参与了突触的mRNA转运和局部翻译的调节，虽然可以识别数百个FMRP靶向的mRNAs，但只有很少的FMRP与肌动蛋白调节蛋白之间的相互作用已被报道和验证。在这篇综述中，我们概述了我们的实验室和其他实验室最近的工作，提供了证据表明，失调的肌动蛋白动力学确实可能是深入了解从认知障碍到自闭症谱系的神经疾病的基础。
Our experiences and memories define who we are, and evidence has accumulated that memory formation is dependent on functional and structural adaptations of synaptic structures in our brain. Especially dendritic spines, the postsynaptic compartments of synapses show a strong structure-to-function relationship and a high degree of structural plasticity. Although the molecular mechanisms are not completely understood, it is known that these modifications are highly dependent on the actin cytoskeleton, the major cytoskeletal component of the spine. Given the crucial involvement of actin in these mechanisms, dysregulations of spine actin dynamics (reflected by alterations in dendritic spine morphology) can be found in a variety of neurological disorders ranging from schizophrenia to several forms of autism spectrum disorders such as fragile X syndrome (FXS). FXS is caused by a single mutation leading to an inactivation of the X-linked fragile X mental retardation 1 gene and loss of its gene product, the RNA-binding protein fragile X mental retardation protein 1 (FMRP), which normally can be found both pre- and postsynaptically. FMRP is involved in mRNA transport as well as regulation of local translation at the synapse, and although hundreds of FMRP-target mRNAs could be identified only a very few interactions between FMRP and actin-regulating proteins have been reported and validated. In this review we give an overview of recent work by our lab and others providing evidence that dysregulated actin dynamics might indeed be at the very base of a deeper understanding of neurological disorders ranging from cognitive impairment to the autism spectrum.