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Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model

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  • Jamal B. Williams

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Qing Cao

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Wei Wang

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Young-Ho Lee

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Luye Qin

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Ping Zhong

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Yong Ren

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Kaijie Ma

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Zhen Yan

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

Abstract

Pleiotropic mechanisms have been implicated in Alzheimer’s disease (AD), including transcriptional dysregulation, protein misprocessing and synaptic dysfunction, but how they are mechanistically linked to induce cognitive deficits in AD is unclear. Here we find that the histone methyltransferase Smyd3, which catalyzes histone H3 lysine 4 trimethylation (H3K4me3) to activate gene transcription, is significantly elevated in prefrontal cortex (PFC) of AD patients and P301S Tau mice, a model of tauopathies. A short treatment with the Smyd3 inhibitor, BCI-121, rescues cognitive behavioral deficits, and restores synaptic NMDAR function and expression in PFC pyramidal neurons of P301S Tau mice. Fbxo2, which encodes an E3 ubiquitin ligase controlling the degradation of NMDAR subunits, is identified as a downstream target of Smyd3. Smyd3-induced upregulation of Fbxo2 in P301S Tau mice is linked to the increased NR1 ubiquitination. Fbxo2 knockdown in PFC leads to the recovery of NMDAR function and cognitive behaviors in P301S Tau mice. These data suggest an integrated mechanism and potential therapeutic strategy for AD.

Suggested Citation

  • Jamal B. Williams & Qing Cao & Wei Wang & Young-Ho Lee & Luye Qin & Ping Zhong & Yong Ren & Kaijie Ma & Zhen Yan, 2023. "Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35749-6
    DOI: 10.1038/s41467-022-35749-6
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    1. Ji-Song Guan & Stephen J. Haggarty & Emanuela Giacometti & Jan-Hermen Dannenberg & Nadine Joseph & Jun Gao & Thomas J. F. Nieland & Ying Zhou & Xinyu Wang & Ralph Mazitschek & James E. Bradner & Ronal, 2009. "HDAC2 negatively regulates memory formation and synaptic plasticity," Nature, Nature, vol. 459(7243), pages 55-60, May.
    2. Pawel K. Mazur & Nicolas Reynoird & Purvesh Khatri & Pascal W. T. C. Jansen & Alex W. Wilkinson & Shichong Liu & Olena Barbash & Glenn S. Van Aller & Michael Huddleston & Dashyant Dhanak & Peter J. Tu, 2014. "SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer," Nature, Nature, vol. 510(7504), pages 283-287, June.
    3. Brookmeyer, R. & Gray, S. & Kawas, C., 1998. "Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset," American Journal of Public Health, American Public Health Association, vol. 88(9), pages 1337-1342.
    4. Vincenzo Sorrentino & Mario Romani & Laurent Mouchiroud & John S. Beck & Hongbo Zhang & Davide D’Amico & Norman Moullan & Francesca Potenza & Adrien W. Schmid & Solène Rietsch & Scott E. Counts & Joha, 2017. "Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity," Nature, Nature, vol. 552(7684), pages 187-193, December.
    5. Caryn S. Ross-Innes & Rory Stark & Andrew E. Teschendorff & Kelly A. Holmes & H. Raza Ali & Mark J. Dunning & Gordon D. Brown & Ondrej Gojis & Ian O. Ellis & Andrew R. Green & Simak Ali & Suet-Feung C, 2012. "Differential oestrogen receptor binding is associated with clinical outcome in breast cancer," Nature, Nature, vol. 481(7381), pages 389-393, January.
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