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Axin2 coupled excessive Wnt-glycolysis signaling mediates social defect in autism spectrum disorders

Summary

Autism spectrum disorder affects social abilities in millions of people, but the underlying causes remain poorly understood. This research discovered that in the brains of people with autism, certain cellular processes that control energy and signaling become overactive, particularly in the region controlling social behavior. The good news is that the researchers found a drug-like compound called XAV939 can restore normal function by blocking the abnormal interaction between two key proteins, potentially offering a new treatment approach.

Background

Autism spectrum disorder (ASD) is characterized by social dysfunction with unclear molecular mechanisms. Although numerous ASD risk genes have been identified, the convergent molecular pathways underlying social deficits remain elusive. Previous studies suggest abnormal Wnt signaling and metabolic dysfunction in ASD.

Objective

To investigate whether aberrant Wnt signaling and glycolysis contribute to ASD-associated synaptic deficiency and social dysfunction. The study aims to identify convergent molecular mechanisms and potential therapeutic targets for social impairment in ASD.

Results

Aberrant Wnt signaling activation and increased glycolysis were found in anterior cingulate cortex (ACC) of both ASD mouse models and human neurons. Axin2 was identified as a convergent point linking Wnt signaling to glycolysis through interaction with ENO1. XAV939, an Axin2 stabilizer, effectively suppressed glycolysis, promoted synaptic maturation, and rescued social deficits in ASD mice.

Conclusion

Excessive neuronal Wnt-glycolysis signaling is an important underlying mechanism for ASD synaptic deficiency and social dysfunction. Axin2 represents a potential therapeutic target, with XAV939 showing promise as a compound for treating ASD-associated social dysfunction with a therapeutic time window from juvenile stages.
  • Published in:EMBO Molecular Medicine,
  • Study Type:Experimental Study,
  • Source: PMID: 37078424, DOI: 10.15252/emmm.202217101
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