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.

中文翻译：

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昼夜节律蛋白 Bmal1 的 O-GlcNAcylation 损害糖尿病小鼠的认知功能。


高血糖诱导的海马神经元损伤已被证明会促进糖尿病认知障碍的发生和发展，但潜在的分子机制仍不清楚。在单细胞 RNA 测序的指导下，我们在这里报道高葡萄糖会增加海马神经元中 Bmal1 的 O-GlcNAcylation。这种糖基化促进 Clock 与 Bmal1 的结合，导致转录因子 Bhlhe41 及其靶标 Dnajb4 的表达。上调的 Dnajb4 反过来导致线粒体 Na + /Ca2+ 交换剂 NCLX 的泛素化和降解，从而诱导线粒体钙过载，从而导致小鼠神经元损伤和认知障碍。值得注意的是，Bhlhe41 下调或用特异性阻断 Bmal1 在 Ser424 上 O-GlcNAcylation 的短肽处理减轻了糖尿病小鼠模型中的这些不良反应。这些数据强调了 O-GlcNAcylation 在生物钟基因表达中的关键作用，并可能有助于糖尿病相关认知障碍的靶向治疗设计。