O-GlcNAcylation of Circadian Clock Protein Bmal1 Impairs Cognitive Function in Diabetic Mice

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2024 Oct 7

PMID 39375536

Authors

Ya Hui

Yuanmei Zhong

Liuyu Kuang

Jingxi Xu

Yuqi Hao

Jingxue Cao

Tianpeng Zheng

Affiliations

Soon will be listed here.

Abstract

Neuronal damage in the hippocampus induced by high glucose has been shown to promote the onset and development of cognitive impairment in diabetes, but the underlying molecular mechanism remains unclear. Guided by single-cell RNA sequencing, we here report that high glucose increases O-GlcNAcylation of Bmal1 in hippocampal neurons. This glycosylation promotes the binding of Clock to Bmal1, resulting in the expression of transcription factor Bhlhe41 and its target Dnajb4. Upregulated Dnajb4 in turn leads to ubiquitination and degradation of the mitochondrial Na + /Ca2+ exchanger NCLX, thereby inducing mitochondrial calcium overload that causes neuronal damage and cognitive impairment in mice. Notably, Bhlhe41 downregulation or treatment with a short peptide that specifically blocks O-GlcNAcylation of Bmal1 on Ser424 mitigated these adverse effects in diabetic mouse models. These data highlight the crucial role of O-GlcNAcylation in circadian clock gene expression and may facilitate the design of targeted therapies for diabetes-associated cognitive impairment.

Citing Articles

Brain O-GlcNAcylation: Bridging physiological functions, disease mechanisms, and therapeutic applications.

Chen L, Jiang H, Licinio J, Wu H Mol Psychiatry. 2025; .

PMID: 40033044 DOI: 10.1038/s41380-025-02943-z.

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