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

Scientists studied mouse brains and found that certain proteins work together to maintain differences between the left and right sides of an important brain region. When one key protein (SH3RF2) was missing, mice showed autism-like behaviors. This happened because removing this protein disrupted the normal balance of other proteins, especially on the left side of the brain. This study suggests that problems with brain asymmetry might contribute to autism development.

This mouse study identified significant differences in protein phosphorylation between left and right brain hemispheres in the striatum, a region affected in autism. Researchers found that SH3RF2, an autism-related protein, forms a complex with other proteins (CaMKII and PPP1CC) to maintain normal brain asymmetry. When SH3RF2 was removed in mice, it disrupted this protein complex, leading to hyperactive CaMKII and abnormal phosphorylation of GluR1 protein, particularly in the left striatum. These molecular changes impaired normal brain lateralization and resulted in autism-like behaviors in mice.

The study proposes this as the first identified molecular mechanism governing brain hemispheric differences in mammals, linking disrupted brain asymmetry to autism development.

Findings suggest brain asymmetry disruption as a potential autism mechanism, offering new therapeutic targets. The CaMKII/PP1 pathway and GluR1 regulation present intervention opportunities. However, translation from mouse models to human autism requires further validation before clinical applications can be developed.

Study conducted only in mice, limiting direct translation to humans. Sample sizes not reported. Unclear if findings apply to all autism subtypes. Long-term effects of SH3RF2 deficiency not evaluated. Requires replication in human studies.

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.