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EF1α-associated protein complexes affect dendritic spine plasticity by regulating microglial phagocytosis in Fmr1 knock-out mice

Molecular Psychiatry (2024)Cite this article

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Abstract

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. There is no specific treatment for FXS due to the lack of therapeutic targets. We report here that Elongation Factor 1α (EF1α) forms a complex with two other proteins: Tripartite motif-containing protein 3 (TRIM3) and Murine double minute (Mdm2). Both EF1α-Mdm2 and EF1α-TRIM3 protein complexes are increased in the brain of Fmr1 knockout mice as a result of FMRP deficiency, which releases the normal translational suppression of EF1α mRNA and increases EF1α protein levels. Increased EF1α-Mdm2 complex decreases PSD-95 ubiquitination (Ub-PSD-95) and Ub-PSD-95-C1q interaction. The elevated level of TRIM3-EF1α complex is associated with decreased TRIM3-Complement Component 3 (C3) complex that inhibits the activation of C3. Both protein complexes thereby contribute to a reduction in microglia-mediated phagocytosis and dendritic spine pruning. Finally, we created a peptide that disrupts both protein complexes and restores dendritic spine plasticity and behavioural deficits in Fmr1 knockout mice. The EF1α-Mdm2 and EF1α-TRIM3 complexes could thus be new therapeutic targets for FXS.

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Fig. 1: Molecular characterization of Mdm2-EF1α and TRIM3- EF1α complexes.
Fig. 2: Both Mdm2 and TRIM3 form protein complexes with EF1α via the L77-D91 region of EF1α.
Fig. 3: TAT-EF1α peptide restores dendritic spine density and plasticity, and reverses behavioural deficits in Fmr1 KO mice.
Fig. 4: TAT-EF1α-pep rescued microglial synaptic pruning deficiency in cortex of Fmr1 KO mice at postnatal day 21 and normalizes the amount of Mdm2-PSD95 complex, ubiquitination of PSD95 and PSD95-C1q interaction in Fmr1 KO mice.
Fig. 5: TAT-EF1α peptide facilitates C3 cleavage through regulating the TRIM3-C3 complex in Fmr1 KO mice.
Fig. 6: Schematic model showing the hypothesized pathway by which Mdm2-EF1α and TRIM3-EF1α regulate dendritic spine density and plasticity.

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The authors declare that data supporting the findings of this study are available from the corresponding author upon request.

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Acknowledgements

The study was supported by Canadian Institute of Health Research (FL), and Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto (FL). FL holds the Tapscott Chair in Schizophrenia studies.

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Authors and Affiliations

  1. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T1R8, Canada

    Ping Su, Shuxin Yan, Frankie Hang Fung Lee, Terence Kai Ying Lai, Anlong Jiang, James Samsom, Albert H. C. Wong & Fang Liu

  2. Department of Anesthesiology, Columbia University Medical Center, New York, NY, 10032, USA

    Kai Chen, Hang Zhou & Guang Yang

  3. Department of Anesthesiology, New York University School of Medicine, New York, NY, 10016, USA

    Lianyan Huang

  4. Institute of Mental Health and Drug Discovery, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China

    Le Wang & Fang Liu

  5. Department of Physiology, University of Toronto, Toronto, ON, M5T 1R8, Canada

    Terence Kai Ying Lai & Fang Liu

  6. Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada

    Albert H. C. Wong & Fang Liu

  7. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5T 1R8, Canada

    Albert H. C. Wong

  8. Institutes of Medical Science, University of Toronto, Toronto, ON, M5T 1R8, Canada

    Albert H. C. Wong & Fang Liu

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  1. Ping Su
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Contributions

FL oversaw and designed the framework of the research. PS designed and performed biochemistry experiments, Golgi-Cox staining, behavioural tests, and analyzed data with help from FHFL (spine density) and TKYL (behavioural tests). KC, LH, HZ, and GY designed, conducted and analyzed the data from in vivo transcranial two-photon imaging. SY, LW, and AJ performed the immunohistochemical analysis. PS, SY, LH, HZ, LW, and AJ prepared the figures. FL, PS, SY, LW, LH, HZ, JS, GY, and AHCW wrote the manuscript.

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Correspondence to Fang Liu.

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Su, P., Yan, S., Chen, K. et al. EF1α-associated protein complexes affect dendritic spine plasticity by regulating microglial phagocytosis in Fmr1 knock-out mice. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-023-02396-2

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