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 elusi...
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202217101 |
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| author | Mengmeng Wang Panpan Xian Weian Zheng Zhenzhen Li Andi Chen Haoxiang Xiao Chao Xu Fei Wang Honghui Mao Han Meng Youyi Zhao Ceng Luo Yazhou Wang Shengxi Wu |
| author_facet | Mengmeng Wang Panpan Xian Weian Zheng Zhenzhen Li Andi Chen Haoxiang Xiao Chao Xu Fei Wang Honghui Mao Han Meng Youyi Zhao Ceng Luo Yazhou Wang Shengxi Wu |
| author_sort | Mengmeng Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e52c2912ea124d4eb4fccce223ad9ddb |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-e52c2912ea124d4eb4fccce223ad9ddb2025-08-20T03:43:25ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-04-0115612010.15252/emmm.202217101Axin2 coupled excessive Wnt‐glycolysis signaling mediates social defect in autism spectrum disordersMengmeng Wang0Panpan Xian1Weian Zheng2Zhenzhen Li3Andi Chen4Haoxiang Xiao5Chao Xu6Fei Wang7Honghui Mao8Han Meng9Youyi Zhao10Ceng Luo11Yazhou Wang12Shengxi Wu13Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research, Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical UniversityAbstract 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.https://doi.org/10.15252/emmm.202217101Axin2glycolysissocial dysfunctionWnt signaling |
| spellingShingle | Mengmeng Wang Panpan Xian Weian Zheng Zhenzhen Li Andi Chen Haoxiang Xiao Chao Xu Fei Wang Honghui Mao Han Meng Youyi Zhao Ceng Luo Yazhou Wang Shengxi Wu Axin2 coupled excessive Wnt‐glycolysis signaling mediates social defect in autism spectrum disorders EMBO Molecular Medicine Axin2 glycolysis social dysfunction Wnt signaling |
| title | Axin2 coupled excessive Wnt‐glycolysis signaling mediates social defect in autism spectrum disorders |
| title_full | Axin2 coupled excessive Wnt‐glycolysis signaling mediates social defect in autism spectrum disorders |
| title_fullStr | Axin2 coupled excessive Wnt‐glycolysis signaling mediates social defect in autism spectrum disorders |
| title_full_unstemmed | Axin2 coupled excessive Wnt‐glycolysis signaling mediates social defect in autism spectrum disorders |
| title_short | Axin2 coupled excessive Wnt‐glycolysis signaling mediates social defect in autism spectrum disorders |
| title_sort | axin2 coupled excessive wnt glycolysis signaling mediates social defect in autism spectrum disorders |
| topic | Axin2 glycolysis social dysfunction Wnt signaling |
| url | https://doi.org/10.15252/emmm.202217101 |
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