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

Jamal B. Williams, Qing Cao, Wei Wang, Young-Ho Lee, Luye Qin, Ping Zhong, Yong Ren, Kaijie Ma and Zhen Yan ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35749-6

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