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Fragile X mental retardation protein interaction with neuronal voltage-gated calcium channels: mechanism and consequences

脆性 X 智力迟钝蛋白与神经元电压门控钙通道的相互作用：机制和后果

基本信息

批准号：
MR/J013285/1
负责人：
Annette Dolphin
金额：
$ 105.83万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FJ013285%2F1
关键词：
Fragile mental retardation protein interaction

项目摘要

Fragile X syndrome is the most common form of inherited severe cognitive impairment, and is usually due to the loss, or sometimes the malfunction, of Fragile X mental retardation protein (FMRP). It is usually caused by a piece of repetitive DNA just before this gene, called the CGG repeat region. This piece of DNA becomes mutated so that it is much longer in Fragile X syndrome, and interferes with the proper function of the gene. The faulty gene is on the X chromosome and is found in 1 in 2500-4000 men and 1 in 6000-8000 women. The prevalence of people carrying this elongation has been estimated to be up to 1 in 130-250 of females. In females carrying pre-mutations (55-200 CGG repeats), the repeat length may expand to become full mutations in their children. However females with a pre-mutation or even a full mutation often do not themselves show symptoms due to a second, normal gene on their other X-chromosome. Normal brain development requires FMRP, and its absence results in developmental delay, cognitive impairment, behavioural problems and motor incoordination. It also results in peripheral symptoms including hypersensitivity to touch, self injury and altered intestinal motility. The loss of FMRP causes no gross brain abnormalities, but connections between nerve cells in the brain are immature and there is a loss of development of these cells. There are some parallels between the autistic features of Fragile X syndrome and other forms of autism. In my research group we have recently found that a protein (CaV2.2) that is commonly found in nerve cells, appears to associate with FMRP. This may relate to some of the behavioural deficits that are characteristic of Fragile X syndrome, particularly the changes that are seen outside the brain, in the regulation of pathways controlling touch and pain.CaV2.2 is a type of calcium ion channel, present in the plasma membrane of nerve cells, which allows these cells to communicate between them. We will probe the interaction between FMRP and CaV2.2 to examine whether how this interaction affects the function of the channels, and the processes in which these channels are involved. We will pay particular attention to communication between pain sensing nerve cells and nerve cells in the spinal cord, which are involved in the transmission of pain signals. It is possible that disruption of this pathway might underlie some of the behavioural problems seen in those with Fragile X syndrome, particularly hypersensitivity to touch. Regulation of CaV2.2 function is highly relevant to touch hypersensitivity in animal models of nerve damage-induced pain, and self-injury behaviour is also one of the behavioural features of in some of those with Fragile X syndrome. In summary, the newly-identified interaction between FMRP and CaV2.2 may play a role in the behavioural features and pathology of Fragile X syndrome, and may at some point in the future lead to novel avenues for treatment.

脆性X综合征是遗传性严重认知障碍的最常见形式，通常是由于脆性X智力低下蛋白（FMRP）的丢失或有时功能障碍。它通常是由该基因之前的一段重复DNA引起的，称为CGG重复区。这段DNA发生突变，使其在脆性X综合征中变得更长，并干扰基因的正常功能。缺陷基因位于X染色体上，在2500-4000名男性和6000-8000名女性中发现1个。据估计，携带这种延长的人的患病率高达1/130-250的女性。在携带前突变（55-200 CGG重复）的女性中，重复长度可能会扩大，在其子女中成为完全突变。然而，具有前突变或甚至完全突变的女性通常不会因另一个X染色体上的第二个正常基因而表现出症状。正常的大脑发育需要FMRP，缺乏FMRP会导致发育迟缓、认知障碍、行为问题和运动不协调。它还导致外周症状，包括对触摸的超敏反应、自我伤害和肠道运动改变。FMRP的缺失不会导致严重的大脑异常，但是大脑中神经细胞之间的连接是不成熟的，并且这些细胞的发育丧失。脆性X染色体综合征的自闭症特征与其他形式的自闭症有一些相似之处。在我的研究小组中，我们最近发现一种在神经细胞中常见的蛋白质（CaV2.2）似乎与FMRP有关。这可能与脆性X综合征的一些特征性行为缺陷有关，特别是在控制触摸和疼痛的通路的调节中在大脑外部看到的变化。CaV2.2是一种钙离子通道，存在于神经细胞的质膜中，允许这些细胞在它们之间进行通信。我们将探索FMRP和CaV2.2之间的相互作用，以研究这种相互作用是否影响通道的功能，以及这些通道参与的过程。我们将特别关注痛觉神经细胞和脊髓神经细胞之间的通讯，这些神经细胞参与疼痛信号的传递。这一途径的中断可能是脆性X综合征患者出现的一些行为问题的基础，特别是对触摸的超敏反应。在神经损伤诱导疼痛的动物模型中，CaV2.2功能的调节与触觉超敏反应高度相关，自伤行为也是某些脆性X综合征患者的行为特征之一。总之，新发现的FMRP和CaV2.2之间的相互作用可能在脆性X综合征的行为特征和病理学中发挥作用，并可能在未来的某个时候导致新的治疗途径。