西班牙巴塞罗那科技学院Xavier Salvatella和Raúl Méndez共同合作，近期取得重要工作进展。他们研究提出，神经元微外显子的错误剪接能促进ASD中CPEB4的聚集。相关研究成果2024年12月4日在线发表于《自然》杂志上。

据介绍，在神经元蛋白质中，通过替代剪接加入微外显子的情况经常发生。这些序列的作用在很大程度上是未知的，其包含程度的变化与神经发育障碍有关。

研究人员之前已经证明，CPEB4（一种通过poly（a）尾部长度的细胞质变化调节翻译的RNA结合蛋白）中24个核苷酸神经元特异性微外显子的减少与特发性自闭症谱系障碍（ASD）有关。为什么需要这种微外显子，以及其包含程度的微小变化如何对ASD相关基因的表达产生显性负面影响，目前尚不清楚。

研究人员发现神经元CPEB4形成凝聚体，在去极化后溶解，这一转变与从翻译抑制到激活的转变有关。微外显子和组氨酸残基簇之间的异型相互作用通过与组氨酸簇之间的同型相互作用竞争来防止CPEB4的不可逆聚集。

总之，这一研究表明，神经元CPEB4需要微外显子来维持CPEB4介导的基因表达，在神经元刺激下的可逆调节。

附：英文原文

Title: Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD

Author: Garcia-Cabau, Carla, Bartomeu, Anna, Tesei, Giulio, Cheung, Kai Chit, Pose-Utrilla, Julia, Pic, Sara, Balaceanu, Andreea, Duran-Arqu, Berta, Fernndez-Alfara, Marcos, Martn, Judit, De Pace, Cesare, Ruiz-Prez, Lorena, Garca, Jess, Battaglia, Giuseppe, Lucas, Jos J., Hervs, Rubn, Lindorff-Larsen, Kresten, Mndez, Ral, Salvatella, Xavier

Issue&Volume: 2024-12-04

Abstract: 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.

DOI: 10.1038/s41586-024-08289-w

Source: https://www.nature.com/articles/s41586-024-08289-w