Volume 35, No 10, Oct 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 10, October 2025: 762-774   |  Open Access

ORIGINAL ARTICLES

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

Yisheng Jiang^1,2,3,* , Feipeng Zhu² , Jie Zhong^2,3 , Xiaomei Sun^2,3 , Yuting Yuan^2,3 , Shuo Wang^2,3 , Haiyang Chen^2,3 , Zhiheng Xu^1,2,3,*

¹Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
²Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
³University of Chinese Academy of Sciences, Beijing, China
Correspondence: Yisheng Jiang(ysjiang01@zju.edu.cn)Zhiheng Xu(zhxu@genetics.ac.cn)

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.

https://doi.org/10.1038/s41422-025-01174-9

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