Deletion of the neuron-specific protein delta-catenin leads to severe cognitive and synaptic dysfunction
Deletion of the neuron-specific protein delta-catenin leads to severe cognitive and synaptic dysfunction
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DOI：
10.1016/j.cub.2004.08.065
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发表时间：
2004-09-21
期刊：
影响因子：
9.2
通讯作者：
Liu, X
中科院分区：
文献类型：
--
作者：
Israely, I;Costa, RM;Liu, X
δ-连环蛋白（δ-连环蛋白）是一种神经元特异性连环蛋白，与粘附和树突状分支有关（1，2）。此外，8-catenin的缺失与Cridu-Chat综合征（CDCS）中精神发育迟滞的严重程度相关，这可能占所有精神发育迟滞个体的1%[3]。有趣的是，δ-连环蛋白首先通过其与早老蛋白-1（PS1）的相互作用而被鉴定，早老蛋白-1是家族性阿尔茨海默病（FAD）中最常突变的分子[4]。我们通过产生具有8-连环蛋白基因的靶向突变（delta-cat（-/-））的小鼠来研究8-连环蛋白的缺失是否足以引起认知功能障碍。我们观察到8-猫（-/-）动物是可行的，并有严重的认知功能障碍。此外，突变小鼠显示海马短期和长期突触可塑性的一系列异常。此外，N-钙粘蛋白和PSD-95，两种与8-连环蛋白相互作用的蛋白质[1，5]，在突变小鼠中显著减少。这些缺陷是严重的，但特异性的，因为β-cat-1-小鼠表现出各种正常行为，表现出正常的基线突触传递，并且具有正常水平的突触粘附蛋白E-钙粘蛋白和β-连环蛋白。这些数据揭示了8-连环蛋白在脑功能中的关键作用，并可能对理解智力迟钝综合征（如Cri-du-Chat）和神经退行性疾病（如阿尔茨海默病）具有重要意义，这些疾病的特征是认知能力下降。
Delta-catenin (8-catenin) is a neuron-specific catenin, which has been implicated in adhesion and dendritic branching (1, 2]. Moreover, deletions of 8-catenin correlate with the severity of mental retardation in Cridu-Chat syndrome (CDCS), which may account for 1% of all mentally retarded individuals [3]. Interestingly, delta-catenin was first identified through its interaction with Presenilin-1 (PS1), the molecule most frequently mutated in familial Alzheimer's Disease (FAD) [4]. We investigated whether deletion of 8-catenin would be sufficient to cause cognitive dysfunction by generating mice with a targeted mutation of the 8-catenin gene (delta-cat(-/-)). We observed that 8-cat(-/-) animals are viable and have severe impairments in cognitive function. Furthermore, mutant mice display a range of abnormalities in hippocampal short-term and long-term synaptic plasticity. Also, N-cadherin and PSD-95, two proteins that interact with 8-catenin [1, 5], are significantly reduced in mutant mice. These deficits are severe but specific because (5-cat-1- mice display a variety of normal behaviors, exhibit normal baseline synaptic transmission, and have normal levels of the synaptic adherens proteins E-cadherin and beta-catenin. These data reveal a critical role for 8-catenin in brain function and may have important implications for understanding mental retardation syndromes such as Cri-du-Chat and neurodegenerative disorders, such as Alzheimer's disease, that are characterized by cognitive decline.