{"title":"Autism-related proteins form a complex to maintain the striatal asymmetry in mice","authors":"Yisheng Jiang, Feipeng Zhu, Jie Zhong, Xiaomei Sun, Yuting Yuan, Shuo Wang, Haiyang Chen, Zhiheng Xu","doi":"10.1038/s41422-025-01174-9","DOIUrl":null,"url":null,"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.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 10","pages":"762-774"},"PeriodicalIF":25.9000,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01174-9.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Research","FirstCategoryId":"99","ListUrlMain":"https://www.nature.com/articles/s41422-025-01174-9","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.