FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability.
FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability.
复制标题
DOI：
10.1159/000506858
复制
发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Trent S
中科院分区：
文献类型：
--
作者：
Clifton NE;Thomas KL;Wilkinson LS;Hall J;Trent S
人们越来越意识到遗传风险变异在介导精神疾病（如精神分裂症和自闭症）易感性方面的作用。许多这些风险变体编码突触蛋白，影响突触后密度的生物途径，并最终影响突触可塑性。脆性X智力低下1（FMR 1）和细胞质脆性X智力低下蛋白（FMRP）相互作用蛋白1（CYFIP 1）包含2个这样的高度外显风险变体的例子，并编码具有共同功能意义的突触蛋白。在这篇综述中，我们讨论了FMRP和CYFIP1的生物学作用，包括它们对（i）蛋白质合成和特定FMRP靶点的调节，（ii）树突和棘形态，以及（iii）突触可塑性形式，如长期抑郁。我们借鉴了一系列临床前研究，这些研究使用FMR 1和CYFIP 1的遗传剂量模型来确定其生物学功能。与此同时，我们讨论了脆性X综合征或15q11.2缺失患者的临床研究如何告知我们对FMRP和CYFIP1的理解，并强调了继续涉及FMRP和CYFIP1的最新精神病基因组研究结果。最后，我们评估了目前我们对FMRP和CYFIP1生物学的理解存在的局限性，以及在为精神疾病开发机制主导的治疗策略之前必须如何解决这些局限性。
There is increasing awareness of the role genetic risk variants have in mediating vulnerability to psychiatric disorders such as schizophrenia and autism. Many of these risk variants encode synaptic proteins, influencing biological pathways of the postsynaptic density and, ultimately, synaptic plasticity. Fragile-X mental retardation 1 (FMR1) and cytoplasmic fragile-X mental retardation protein (FMRP)-interacting protein 1 (CYFIP1) contain 2 such examples of highly penetrant risk variants and encode synaptic proteins with shared functional significance. In this review, we discuss the biological actions of FMRP and CYFIP1, including their regulation of (i) protein synthesis and specifically FMRP targets, (ii) dendritic and spine morphology, and (iii) forms of synaptic plasticity such as long-term depression. We draw upon a range of preclinical studies that have used genetic dosage models of FMR1 and CYFIP1 to determine their biological function. In parallel, we discuss how clinical studies of fragile X syndrome or 15q11.2 deletion patients have informed our understanding of FMRP and CYFIP1, and highlight the latest psychiatric genomic findings that continue to implicate FMRP and CYFIP1. Lastly, we assess the current limitations in our understanding of FMRP and CYFIP1 biology and how they must be addressed before mechanism-led therapeutic strategies can be developed for psychiatric disorders.