CNTNAP2 intracellular domain (CICD) generated by γ-secretase cleavage improves autism-related behaviors.
CNTNAP2 intracellular domain (CICD) generated by γ-secretase cleavage improves autism-related behaviors.
复制标题
DOI：
10.1038/s41392-023-01431-6
复制
发表时间：
2023-06-05
影响因子：
39.3
通讯作者：
Li, Jia-Da
中科院分区：
文献类型：
--
作者：
Zhang, Jing;Cai, Fang;Lu, Renbin;Xing, Xiaoliang;Xu, Lu;Wu, Kunyang;Gong, Zishan;Zhang, Qing;Zhang, Yun;Xing, Mengen;Song, Weihong;Li, Jia-Da
自闭症谱系障碍（autism spectrum disorders，ASD）是儿童中最常见的神经发育障碍，以语言发育、社会交往、重复性行为或刻板兴趣为特征。Contactin相关蛋白样2（CNTNAP 2）编码一个具有1331个氨基酸残基的单一跨膜蛋白（CNTNAP 2），是一个被广泛验证的ASD易感基因。cntnap 2缺陷小鼠也表现出核心自闭症相关行为，包括社交缺陷和重复行为。然而，CNTNAP 2和ASD功能障碍的细胞机制仍然难以捉摸。在本研究中，我们发现CNTNAP 2的跨膜结构域中的一个基序与淀粉样β前体蛋白（APP）的γ-分泌酶切割位点高度同源，提示CNTNAP 2可能经历蛋白水解切割。进一步的生物化学分析表明，CNTNAP 2被γ-分泌酶切割以产生CNTNAP 2胞内结构域（CICD）。将CICD病毒递送到Cntnap 2缺陷（Cntnap 2 −/−）小鼠的内侧前额叶皮层（mPFC）使ASD相关行为的缺陷正常化，包括社交缺陷和重复行为。此外，CICD促进钙/钙调素依赖性丝氨酸蛋白激酶（CASK）的核转位，以调节基因的转录，如Prader Willi综合征基因Necdin。Necdin缺陷导致小鼠的社会互动减少，而Necdin在mPFC中的病毒表达使Cntnap 2 −/−小鼠的社会偏好缺陷正常化。因此，我们的研究结果揭示了CICD的关键功能，并强调了CNTNAP 2-CASK-Necdin信号通路在ASD中的作用。
As the most prevalent neurodevelopmental disorders in children, autism spectrum disorders (ASD) are characterized by deficits in language development, social interaction, and repetitive behaviors or inflexible interests. Contactin associated protein like 2 (CNTNAP2), encoding a single transmembrane protein (CNTNAP2) with 1331 amino acid residues, is a widely validated ASD-susceptible gene. Cntnap2-deficient mice also show core autism-relevant behaviors, including the social deficits and repetitive behavior. However, the cellular mechanisms underlying dysfunction CNTNAP2 and ASD remain elusive. In this study, we found a motif within the transmembrane domain of CNTNAP2 was highly homologous to the γ-secretase cleavage site of amyloid-β precursor protein (APP), suggesting that CNTNAP2 may undergo proteolytic cleavage. Further biochemical analysis indicated that CNTNAP2 is cleaved by γ-secretase to produce the CNTNAP2 intracellular domain (CICD). Virally delivery of CICD to the medial prefrontal cortex (mPFC) in Cntnap2-deficient (Cntnap2−/−) mice normalized the deficit in the ASD-related behaviors, including social deficit and repetitive behaviors. Furthermore, CICD promoted the nuclear translocation of calcium/calmodulin-dependent serine protein kinase (CASK) to regulate the transcription of genes, such as Prader Willi syndrome gene Necdin. Whereas Necdin deficiency led to reduced social interaction in mice, virally expression of Necdin in the mPFC normalized the deficit in social preference of Cntnap2−/− mice. Our results thus reveal a critical function of CICD and highlight a role of the CNTNAP2-CASK-Necdin signaling pathway in ASD.
登录
查看更多内容
影响因子：
56.9
作者：
Cao, XW;Südhof, TC
通讯作者：
Südhof, TC
影响因子：
30.8
作者：
Gérard, M;Hernandez, L;Stewart, CL
通讯作者：
Stewart, CL
影响因子：
64.8
作者：
De Strooper, B;Saftig, P;Van Leuven, F
通讯作者：
Van Leuven, F
影响因子：
11
作者：
Gao R;Piguel NH;Melendez-Zaidi AE;Martin-de-Saavedra MD;Yoon S;Forrest MP;Myczek K;Zhang G;Russell TA;Csernansky JG;Surmeier DJ;Penzes P
通讯作者：
Penzes P
影响因子：
56.9
作者：
Bidinosti, Michael;Botta, Paolo;Galimberti, Ivan
通讯作者：
Galimberti, Ivan