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論文標(biāo)題：Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD 作者：Garcia-Cabau, Carla, Bartomeu, Anna, Tesei, Giulio, Cheung, Kai Chit, Pose-Utrilla, Julia, Picó, Sara, Balaceanu, Andreea, Duran-Arqué, Berta, Fernández-Alfara, Marcos, Martín, Judit, De Pace, Cesare, Ruiz-Pérez, Lorena, García, Jesús, Battaglia, Giuseppe, Lucas, José J., Hervás, Rubén, Lindorff-Larsen, Kresten, Méndez, Raúl, Salvatella, Xavier 查看更多 期刊：Nature 發(fā)表時(shí)間：2024/12/04 數(shù)字識(shí)別碼：10.1038/s41586-024-08289-w 摘要：The inclusion of microexons by alternative splicing occurs frequently in neuronal proteins. The roles of these sequences are largely unknown, and changes in their degree of inclusion are associated with neurodevelopmental disorders1. We have previously shown that decreased inclusion of a 24-nucleotide neuron-specific microexon in CPEB4, a RNA-binding protein that regulates translation through cytoplasmic changes in poly(A) tail length, is linked to idiopathic autism spectrum disorder (ASD)2. Why this microexon is required and how small changes in its degree of inclusion have a dominant-negative effect on the expression of ASD-linked genes is unclear. Here we show that neuronal CPEB4 forms condensates that dissolve after depolarization, a transition associated with a switch from translational repression to activation. Heterotypic interactions between the microexon and a cluster of histidine residues prevent the irreversible aggregation of CPEB4 by competing with homotypic interactions between histidine clusters. We conclude that the microexon is required in neuronal CPEB4 to preserve the reversible regulation of CPEB4-mediated gene expression in response to neuronal stimulation. 查看更多 摘要翻譯（由計(jì)算機(jī)程序完成，僅供參考，內(nèi)容以英文原文為準(zhǔn)）： 通過(guò)選擇性剪接包含微泡的情況經(jīng)常發(fā)生；在神經(jīng)元蛋白中。這些序列的作用在很大程度上是未知的，其包含程度的變化與神經(jīng)發(fā)育障礙有關(guān)1。我們之前已經(jīng)證明，CPEB4（一種通過(guò)poly（a）尾部長(zhǎng)度的細(xì)胞質(zhì)變化調(diào)節(jié)翻譯的RNA結(jié)合蛋白）中24個(gè)核苷酸神經(jīng)元特異性微泡的減少與特發(fā)性自閉癥譜系障礙（ASD）2有關(guān)。為什么需要這種微電子，以及其包含程度的微小變化如何對(duì)ASD連鎖基因的表達(dá)產(chǎn)生顯性負(fù)面影響，目前尚不清楚。在這里，我們發(fā)現(xiàn)神經(jīng)元CPEB4形成凝聚體，在去極化后溶解，這一轉(zhuǎn)變與從翻譯抑制到激活的轉(zhuǎn)變有關(guān)。微子和組氨酸殘基簇之間的異型相互作用通過(guò)與組氨酸簇之間的同型相互作用競(jìng)爭(zhēng)來(lái)防止CPEB4的不可逆聚集。我們得出結(jié)論，神經(jīng)元CPEB4需要微電子來(lái)維持CPEB4介導(dǎo)的基因表達(dá)在神經(jīng)元刺激下的可逆調(diào)節(jié)。 查看更多 |
