The association of GPR85 with PSD-95-neuroligin complex and autism spectrum disorder: a molecular analysis.
The association of GPR85 with PSD-95-neuroligin complex and autism spectrum disorder: a molecular analysis.
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DOI：
10.1186/s13229-015-0012-5
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发表时间：
2015
期刊：
影响因子：
6.2
通讯作者：
Momoi T
中科院分区：
文献类型：
--
作者：
Fujita-Jimbo E;Tanabe Y;Yu Z;Kojima K;Mori M;Li H;Iwamoto S;Yamagata T;Momoi MY;Momoi T
自闭症谱系障碍（ASD）具有复杂的遗传病因。精神分裂症和ASD共有一些症状和突变基因，包括神经连接素（NLGN）、神经节苷脂（NRXN）、SH 3和多锚蛋白重复结构域蛋白（SHANK）。ASD的分子发病机制知之甚少。其中一个可能的分子发病机制是通过突触后密度蛋白/果蝇盘大肿瘤抑制因子/闭锁小带-1蛋白（PDZ）结合与NLGN-PSD-95-SHANK复合物连接的兴奋性和抑制性受体的不平衡。在本研究中，我们将GPR 85作为ASD的候选基因，因为GPR 85的C-末端氨基酸序列[Thr-Cys-Val-Ile（YCVI）]被归类为II型PDZ结合基序，并且GPR 85是精神分裂症的危险因素。GPR 85是一种孤儿受体，调节神经和突触可塑性，并调节包括学习和记忆在内的多种行为。在寻找与GPR 85相关的分子时，我们发现GPR 85与脑内NLGN相关的突触后密度蛋白（PSD）-95相关。我们通过下拉分析和免疫印迹分析检测了与GPR 85 C-末端序列相关的蛋白质，并在ASD患者中寻找GPR 85基因的突变。我们使用免疫染色检测突变的GPR 85的细胞内定位及其对细胞和神经元形态的影响。GPR 85的C端序列与PSD-95在PDZ 1处相互作用，而NLGN与PSD-95在PDZ 3处相互作用。两名来自独立日本家族的ASD男性患者在GPR 85保守位点具有遗传性错义突变：一名为T1033 C（M152 T），另一名为G1239 T（V221 L）。这些突变位于与G蛋白相互作用和信号转导相关的结构域。与野生型GPR 85相比，突变的GPR 85更优先地积累，引起内质网应激，并扰乱海马神经元树突的形成。GPR 85与PSD-95相关，PSD-95与NLGN相关，NLGN与ASD相关。在ASD患者中检测到的携带突变的GPR 85干扰树突形成，这可能是通过相关的NLGN-PSD-95受体复合物导致ASD分子发病的候选者。本文的在线版本（doi：10.1186/s13229-015-0012-5）包含补充材料，可供授权用户使用。
Autism spectrum disorder (ASD) has a complex genetic etiology. Some symptoms and mutated genes, including neuroligin (NLGN), neurexin (NRXN), and SH3 and multiple ankyrin repeat domains protein (SHANK), are shared by schizophrenia and ASD. Little is known about the molecular pathogenesis of ASD. One of the possible molecular pathogenesis is an imbalance of excitatory and inhibitory receptors linked with the NLGN-PSD-95-SHANK complex via postsynaptic density protein/Drosophila disc large tumor suppressor/zonula occludens-1 protein (PDZ) binding. In the present study, we focused on GPR85 as a candidate gene for ASD because the C-terminal amino acid sequence of GPR85 [Thr-Cys-Val-Ile (YCVI)] is classified as a type II PDZ-binding motif, and GPR85 is a risk factor for schizophrenia. GPR85 is an orphan receptor that regulates neural and synaptic plasticity and modulates diverse behaviors, including learning and memory. While searching for molecules that associate with GPR85, we found that GPR85 was associated with postsynaptic density protein (PSD)-95 linked with NLGN in the brain. We examined the proteins that associate with the C-terminal sequence of GPR85 by pull-down assay and immunoblot analysis and searched for a mutation of the GPR85 gene in patients with ASD. We used immunostaining to examine the intracellular localization of mutated GPR85 and its influence on the morphology of cells and neurons. The C-terminal sequence of GPR85 interacted with PSD-95 at PDZ1, while NLGN interacted with PSD-95 at PDZ3. Two male patients with ASD from independent Japanese families possessed inherited missense mutations at conserved sites in GPR85: one had T1033C (M152T) and the other had G1239T (V221L). These mutations were located in a domain related to G protein interaction and signal transduction. In contrast to wild-type GPR85, mutated GPR85 was more preferentially accumulated, causing endoplasmic reticulum stress, and disturbed the dendrite formation of hippocampal neurons. GPR85 associated with the PSD-95 linked with NLGN, which is related to ASD. GPR85 carrying the mutations detected in ASD patients disturbed dendrite formation that could be the candidate for molecular pathogenesis of ASD through the associated NLGN-PSD-95 receptor complex. The online version of this article (doi:10.1186/s13229-015-0012-5) contains supplementary material, which is available to authorized users.
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影响因子：
4.4
作者：
Marazziti, D;Golini, E;TocchiniValentini, GP
通讯作者：
TocchiniValentini, GP
影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
帕金森氏病相关的G蛋白偶联受体37（GPR37/PAELR）突变与自闭症谱系障碍有关。
影响因子：
3.7
作者：
Fujita-Jimbo E;Yu ZL;Li H;Yamagata T;Mori M;Momoi T;Momoi MY
通讯作者：
Momoi MY
影响因子：
5.3
作者：
Gauthier J;Siddiqui TJ;Huashan P;Yokomaku D;Hamdan FF;Champagne N;Lapointe M;Spiegelman D;Noreau A;Lafrenière RG;Fathalli F;Joober R;Krebs MO;DeLisi LE;Mottron L;Fombonne E;Michaud JL;Drapeau P;Carbonetto S;Craig AM;Rouleau GA
通讯作者：
Rouleau GA
DOI：
10.1083/jcb.200207050
发表时间：
2002-10-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Poliak S;Matlis S;Ullmer C;Scherer SS;Peles E
通讯作者：
Peles E