SIRT1 deficiency increases O-GlcNAcylation of tau, mediating synaptic tauopathy
SIRT1 deficiency increases O-GlcNAcylation of tau, mediating synaptic tauopathy
复制标题
SIRT1 缺陷增加 tau 蛋白的 O-GlcNAc 酰化，介导突触 tau 病
DOI：
10.1038/s41380-022-01689-2
复制
发表时间：
2022-07-25
影响因子：
11
通讯作者：
Qian, Wei
中科院分区：
文献类型：
--
作者：
Yin, Xiaomin;Li, Yuanyuan;Qian, Wei
微管相关蛋白tau的过度磷酸化与几种神经退行性疾病有关，包括阿尔茨海默病（AD），统称为tau病。然而，tau蛋白与突触功能障碍和记忆障碍相关的机制尚不清楚。为了解决这个问题，我们构建了一个脑特异性SIRT1 （SIRT1 flox/Cre +）缺失的小鼠模型。本研究表明，SIRT1 flox/Cre+小鼠大脑中O-GlcNAcase （OGA）降低和O-GlcNAc转移酶（OGT）蛋白水平升高引发tau位点特异性磷酸化的增加与tau的o - glcnac酰化增强相结合。小鼠大脑中SIRT1的缺失改变了位点特异性磷酸化tau的突触体分布。通过SIRT1 flox/Cre+小鼠揭示树突状脊柱缺损和突触功能障碍引起的学习和记忆缺陷。我们的研究结果为SIRT1作为临床牛头病变的潜在治疗靶点提供了证据。
Hyperphosphorylation of the microtubule associated protein tau is associated with several neurodegenerative diseases including Alzheimer's Disease (AD), collectively referred to as tauopathies. However, the mechanisms by which tau is linked to synaptic dysfunction and memory impairment remain unclear. To address this question, we constructed a mouse model with brain-specific deficiency of SIRT1 (SIRT1 flox/Cre +). Here, we show that increase of site-specific phosphorylation of tau is coupled with the strengthened O-GlcNAcylation of tau triggered by reduced O-GlcNAcase (OGA) and increased O-GlcNAc transferase (OGT) protein level in the brain of SIRT1 flox/Cre+ mice. SIRT1 deletion in mice brain changes the synaptosomal distribution of site-specific phospho-tau. Learning and memory deficiency induced by dendritic spine deficits and synaptic dysfunction are revealed via SIRT1 flox/Cre+ mice. Our results provide evidence for SIRT1 as a potential therapeutic target in clinical tauopathies.