Toward fulfilling the promise of molecular medicine in fragile X syndrome.
Toward fulfilling the promise of molecular medicine in fragile X syndrome.
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DOI：
10.1146/annurev-med-061109-134644
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发表时间：
2011
影响因子：
10.5
通讯作者：
Bear MF
中科院分区：
文献类型：
--
作者：
Krueger DD;Bear MF
脆性X综合征（FXS）是最常见的遗传性精神发育迟滞形式，也是自闭症的主要已知原因。它是由脆性X智力低下蛋白（FMRP）表达缺失引起的，FMRP是一种负调节蛋白质合成的RNA结合蛋白。在神经元中，多条证据表明，突触处的蛋白质合成是由第1组代谢型谷氨酸受体（Gp1 mGluRs）的激活触发的，并且在不存在FMRP的情况下，激活这些受体的许多功能后果被改变。这些观察结果导致了Gp1 mGluRs下游蛋白质合成过度是FXS核心致病机制的理论。这种过量可以通过减少Gp1 mGluRs的信号传导来纠正，许多研究表明，特别是mGluR5的抑制可以改善FXS动物模型中的多种突变表型。目前正在进行基于这种治疗策略的临床试验。因此，FXS有望成为第一个自下而上开发矫正治疗的神经行为障碍：从动物的基因鉴定到病理生理学，再到人类的新疗法。从FXS和其他自闭症相关的单基因疾病中获得的见解也可能有助于确定特发性自闭症的分子机制和潜在治疗方法。
Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism.
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DOI：
10.1073/pnas.89.10.4363
发表时间：
1992-05-15
影响因子：
11.1
作者：
DUDEK, SM;BEAR, MF
通讯作者：
BEAR, MF
影响因子：
2.5
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Kuhn, R
DOI：
10.1097/dbp.0b013e31817dc447
发表时间：
2008-08-01
影响因子：
2.4
作者：
Berry-Kravis, Elizabeth;Sumis, Allison;Greenough, William T.
通讯作者：
Greenough, William T.