Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by differences in how people interact or communicate with others, as well as restricted interests and repetitive patterns of behavior. Past studies have observed specific differences in brain development in many autistic individuals, which typically first emerge during the early stages of life.
Some research has also suggested that molecular processes, such as the synthesis of proteins inside cells, play a key role in autism. However, the molecular underpinnings of ASD have not yet been clearly elucidated.
Researchers at Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University and Jiaying University recently set out to explore the possible role of protein synthesis, the process via which cells create proteins based on genetic instructions, in autism. To do this, they studied a mouse model of ASD, collecting and examining brain tissue samples from mice exhibiting autism-like behavior, while also performing molecular analyses to measure gene activity and protein production. The findings are published in the journal Molecular Psychiatry.
“Perturbed protein synthesis plays a crucial role in the pathogenesis of ASD, but the altered translational pattern and underlying mechanism remain poorly understood,” wrote Miaoqi Huang, Han Ye and their colleagues. “We identified an exaggeration of global protein synthesis in the cerebral cortex of offspring mice following prenatal exposure of valproic acid (VPA), a well-established ASD model.”
Studying a mouse model of ASD
Huang, Ye and their colleagues set out to explore the synthesis of proteins in the brains of mice that presented autism-like behaviors. These mice were exposed to a drug known as valproic acid (VPA) while they were still in the womb, which is known to produce ASD-like traits.
The researchers analyzed tissue taken from the mice’s cerebral cortex, the outer layer of the brain. They carried out various molecular analyses aimed at detecting gene activity, the synthesis of proteins, which proteins were produced and in what amounts.
“Integrative analysis of polyribosome-based translatome and proteome data revealed remarkable upregulation of ribosomal and mitochondrial genes in VPA-exposed cortex at both translational and protein levels, but not transcriptional levels,” wrote the authors.
“Further analysis pinpoints that overactivation of the translation initiation factor eIF4E causes the aberrant translatome and mitochondrial impairments in VPA-exposed cortex. Pharmacological inhibition of eIF4E phosphorylation during juvenile displayed persistent effectiveness in mitigating ASD-like social deficits and stereotyped behavior in VPA mice until adulthood.”
The team’s analyses revealed that the mice exhibiting ASD-like behaviors produced more proteins without presenting increased gene transcription. The observed differences in the synthesis of proteins appeared to be partly driven by an overactivation of eIF4E (eukaryotic initiation factor 4E), a protein that regulates the production of other proteins.
“Collectively, the findings demonstrate that eIF4E overactivation leads to imbalanced protein synthesis that favors translation of ribosomal and mitochondrial genes, causing core ASD-like behaviors,” wrote Huang, Ye and their colleagues.
A possible therapeutic target
In some of their experiments, the researchers also blocked the activation of eIF4E in the mice, using drugs that prevented the protein from becoming overactive. Interestingly, they found that when the production of this protein decreased, the mice started exhibiting fewer autism-like behaviors.
The researchers reduced eIF4E activation when the mice were young, yet the observed behavioral changes persisted when they reached adulthood. This suggests that eIF4E contributes to the emergence of autism-like behaviors in the examined mouse model and may also play a role in humans.
If they are validated in humans, the findings gathered by Huang, Ye and their colleagues could potentially inform future research focusing on ASD. In the future, drugs targeting EIF4E and thus reducing protein synthesis in brain cells could potentially moderate some of the repetitive behaviors or differences in social interactions associated with ASD.
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Publication details
Miaoqi Huang et al, Correction of eIF4E overactivation rescues translatome imbalance and core ASD-like behaviors in valproic acid-induced offspring mice, Molecular Psychiatry (2026). DOI: 10.1038/s41380-026-03517-3.
Journal information:
Molecular Psychiatry
Key medical concepts
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