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

Abstract

Social dysfunction is the core syndrome of autism spectrum disorder (ASD) and lacks effective medicine. Although numerous risk genes and relevant environmental factors have been identified, the convergent molecular mechanism underlying ASD‐associated social dysfunction remains largely elusive. Here, we report aberrant activation of canonical Wnt signaling and increased glycolysis in the anterior cingulate cortex (ACC, a key brain region of social function) of two ASD mouse models (Shank3−/− and valproic acid‐treated mice) and their corresponding human neurons. Overexpressing β‐catenin in the ACC of wild‐type mice induces both glycolysis and social deficits. Suppressing glycolysis in ASD mice partially rescued synaptic and social phenotype. Axin2, a key inhibitory molecule in Wnt signaling, interacts with the glycolytic enzyme enolase 1 (ENO1) in ASD neurons. Surprisingly, an Axin2 stabilizer, XAV939, effectively blocked Axin2/ENO1 interaction, switched glycolysis/oxidative phosphorylation balance, promoted synaptic maturation, and rescued social function. These data revealed excessive neuronal Wnt‐glycolysis signaling as an important underlying mechanism for ASD synaptic deficiency, indicating Axin2 as a potential therapeutic target for social dysfunction.

ENO1 promotes trophoblast invasion regulated by E2F8 in recurrent miscarriage

“…For example, it has been reported that ENO1 interacts with hepatocyte growth factor receptor (HGFR) and activates HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt co‐receptor low‐density lipoprotein receptor‐related protein 5 and 6 26 . Additionally, Axin2, a key inhibitory molecule in Wnt signaling, interacts with the ENO1 in neurons of autism spectrum disorders 27 . Furthermore, SFRPs are among the most studied Wnt inhibitors 28 .…”

“…26 Additionally, Axin2, a key inhibitory molecule in Wnt signaling, interacts with the ENO1 in neurons of autism spectrum disorders. 27 Furthermore, SFRPs are among the most studied Wnt inhibitors. 28 Research has shown that the expression of βcatenin was significantly decreased at both the mRNA and protein levels in the villi and decidua of the recurrent spontaneous abortion group compared with the normal control group.…”