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

Autor: Su P; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T1R8, Canada., Yan S; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T1R8, Canada., Chen K; Department of Anesthesiology, Columbia University Medical Center, New York, NY, 10032, USA., Huang L; Department of Anesthesiology, New York University School of Medicine, New York, NY, 10016, USA., Wang L; 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., Lee FHF; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T1R8, Canada., Zhou H; Department of Anesthesiology, Columbia University Medical Center, New York, NY, 10032, USA., Lai TKY; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T1R8, Canada.; Department of Physiology, University of Toronto, Toronto, ON, M5T 1R8, Canada., Jiang A; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T1R8, Canada., Samsom J; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T1R8, Canada., Wong AHC; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T1R8, Canada.; Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5T 1R8, Canada.; Institutes of Medical Science, University of Toronto, Toronto, ON, M5T 1R8, Canada., Yang G; Department of Anesthesiology, Columbia University Medical Center, New York, NY, 10032, USA., Liu F; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T1R8, Canada. fang.liu@camh.ca.; 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. fang.liu@camh.ca.; Department of Physiology, University of Toronto, Toronto, ON, M5T 1R8, Canada. fang.liu@camh.ca.; Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada. fang.liu@camh.ca.; Institutes of Medical Science, University of Toronto, Toronto, ON, M5T 1R8, Canada. fang.liu@camh.ca.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 Apr; Vol. 29 (4), pp. 1099-1113. Date of Electronic Publication: 2024 Jan 11.
DOI: 10.1038/s41380-023-02396-2
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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