近日，中国科学院遗传与发育生物学研究所许执恒团队的研究开发出了自闭症相关蛋白形成复合体，维持小鼠纹状体的不对称性。相关论文发表在2025年9月2日出版的《细胞研究》杂志上。

通过对双侧纹状体的蛋白质组学和磷酸化蛋白质组学分析，课题组研究人员发现了显著的磷酸化不对称。双侧纹状体是重要脑功能的中心，也是自闭症病理生理的共同节点。特别是，左纹状体的磷酸化过程似乎更容易受到干扰。值得注意的是，SH3RF2，其单拷贝敲除导致小鼠自闭症谱系障碍（ASD）样行为，在纹状体中唯一表达，与CaMKII（一种ASD相关蛋白）和PPP1CC形成复合物。

SH3RF2的缺失扰乱了CaMKII/PP1“开关”，导致CaMKII过度活跃，其底物GluR1磷酸化增加。在Sh3rf2缺失的小鼠中，左侧纹状体中GluR1-Ser831磷酸化的升高及其突触后膜定位的异常可能会损害纹状体神经元的功能侧化，并导致自闭症样行为。这项研究首次揭示了哺乳动物大脑偏侧化的分子机制，将其损伤与自闭症的发展和治疗策略联系起来。

研究人员表示，大脑的两个半球表现出深刻的偏侧化，但其潜在机制仍不清楚。

附：英文原文

Title: Autism-related proteins form a complex to maintain the striatal asymmetry in mice

Author: Jiang, Yisheng, Zhu, Feipeng, Zhong, Jie, Sun, Xiaomei, Yuan, Yuting, Wang, Shuo, Chen, Haiyang, Xu, Zhiheng

Issue&Volume: 2025-09-02

Abstract: The brain’s hemispheres exhibit profound lateralization, yet the underlying mechanisms remain elusive. Using proteomic and phosphoproteomic analyses of the bilateral striatum — a hub for important brain functions and a common node of autism pathophysiology — we identified significant phosphorylation asymmetries. Particularly, the phosphorylation processes in the left striatum appear more prone to disturbance. Notably, SH3RF2, whose single-copy knockout leads to autism spectrum disorder (ASD)-like behaviors in mice, is uniquely expressed in the striatum, forming a complex with CaMKII (an ASD-associated protein) and PPP1CC. Loss of SH3RF2 disturbs the CaMKII/PP1 “switch”, resulting in hyperactivity of CaMKII and increased phosphorylation of its substrate GluR1. In Sh3rf2-deficient mice, heightened GluR1-Ser831 phosphorylation and its aberrant postsynaptic membrane localization in the left striatum may impair the functional lateralization of striatal neurons and contribute to autism-like behaviors. This study unveils the first molecular mechanism governing brain lateralization in mammals, linking its impairment to autism development and treatment strategies.

DOI: 10.1038/s41422-025-01174-9

Source: https://www.nature.com/articles/s41422-025-01174-9