Autism spectrum disorder is related to endoplasmic reticulum stress induced by mutations in the synaptic cell adhesion molecule, CADM1.
Autism spectrum disorder is related to endoplasmic reticulum stress induced by mutations in the synaptic cell adhesion molecule, CADM1.
复制标题
DOI：
10.1038/cddis.2010.23
复制
发表时间：
2010-06-03
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
自闭症谱系障碍（ASD）是一种神经发育障碍，其分子发病机制尚不清楚。最近的一个分子焦点是突变的神经连接素3，神经连接素3（R451 C），在获得功能的研究，并在诱导损伤的突触功能的作用，但内质网（ER）的突变分子诱导的压力也值得调查。我们之前在ASD患者的突触细胞粘附分子1（CADM 1）编码基因中发现了两个错义突变，H246 N和Y251 S，包括突变CADM 1的切割及其细胞内积累。在这项研究中，我们发现突变的CADM 1在体外表现出轻微的嗜同性相互作用，但其大部分相互作用仍然存在。突变的CADM 1也表现出形态异常，包括较短的树突和神经元中受损的突触发生。野生型CADM 1部分定位于C2 C5细胞的ER，而突变的CADM 1主要积累在ER中，尽管对具有化学伴侣活性的4-苯基丁酸和具有促进聚合蛋白降解活性的雷帕霉素具有不同的敏感性。模型分析表明，突变和构象改变之间的直接关系。突变的CADM 1和神经连接素3（R451 C）均诱导C/EBP同源蛋白（CHOP）（一种ER应激标志物）的上调，这表明除了运输障碍之外，CHOP上调也可能参与ASD发病机制。
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an unknown molecular pathogenesis. A recent molecular focus has been the mutated neuroligin 3, neuroligin 3(R451C), in gain-of-function studies and for its role in induced impairment of synaptic function, but endoplasmic reticulum (ER) stress induced by mutated molecules also deserves investigation. We previously found two missense mutations, H246N and Y251S, in the gene-encoding synaptic cell adhesion molecule-1 (CADM1) in ASD patients, including cleavage of the mutated CADM1 and its intracellular accumulation. In this study, we found that the mutated CADM1 showed slightly reduced homophilic interactions in vitro but that most of its interactions persist. The mutated CADM1 also showed morphological abnormalities, including shorter dendrites, and impaired synaptogenesis in neurons. Wild-type CADM1 was partly localized to the ER of C2C5 cells, whereas mutated CADM1 mainly accumulated in the ER despite different sensitivities toward 4-phenyl butyric acid with chemical chaperone activity and rapamycin with promotion activity for degradation of the aggregated protein. Modeling analysis suggested a direct relationship between the mutations and the conformation alteration. Both mutated CADM1 and neuroligin 3(R451C) induced upregulation of C/EBP-homologous protein (CHOP), an ER stress marker, suggesting that in addition to the trafficking impairment, this CHOP upregulation may also be involved in ASD pathogenesis.
登录
查看更多内容
影响因子：
3.5
作者：
Fujita, Eriko;Kouroku, Yoriko;Momoi, Takashi
通讯作者：
Momoi, Takashi
影响因子：
56.9
作者：
Biederer, T;Sara, Y;Südhof, TC
通讯作者：
Südhof, TC
影响因子：
16.2
作者：
Chen, A;Muzzio, IA;Kandel, ER
通讯作者：
Kandel, ER
影响因子：
5.3
作者：
Comoletti, D;De Jaco, A;Taylor, P
通讯作者：
Taylor, P
影响因子：
64.5
作者：
Costa-Mattioli, Mauro;Gobert, Delphine;Sonenberg, Nahum
通讯作者：
Sonenberg, Nahum