Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model.
Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model.
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DOI：
10.1038/s41467-022-35749-6
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发表时间：
2023-01-06
影响因子：
16.6
通讯作者：
Yan, Zhen
中科院分区：
文献类型：
--
作者：
Williams, Jamal B.;Cao, Qing;Wang, Wei;Lee, Young-Ho;Qin, Luye;Zhong, Ping;Ren, Yong;Ma, Kaijie;Yan, Zhen
多效机制与阿尔茨海默病（AD）有关，包括转录失调、蛋白质错误加工和突触功能障碍，但它们如何在机制上与AD中诱导认知缺陷联系尚不清楚。在这里，我们发现，组蛋白甲基转移酶Smyd 3，催化组蛋白H3赖氨酸4三甲基化（H3 K4 me 3），以激活基因转录，显着升高，在前额叶皮层（PFC）的AD患者和P301 S Tau小鼠，一个模型的Tau病变。用Smyd 3抑制剂BCI-121进行短时间治疗可挽救认知行为缺陷，并恢复P301 S Tau小鼠PFC锥体神经元中的突触NMDAR功能和表达。Fbxo 2编码控制NMDAR亚基降解的E3泛素连接酶，被鉴定为Smyd 3的下游靶标。Smyd 3诱导的P301 S Tau小鼠中Fbxo 2上调与NR 1泛素化增加有关。PFC中Fbxo 2敲低导致P301 S Tau小鼠中NMDAR功能和认知行为的恢复。这些数据提示了AD的综合机制和潜在的治疗策略。威廉姆斯等人的研究表明，靶向异常组蛋白修饰酶Smyd 3可以挽救阿尔茨海默病小鼠模型中的NMDAR和认知缺陷。它突出了表观遗传治疗在神经退行性疾病中的潜力。
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. The study by Williams et al shows targeting the aberrant histone modifying enzyme Smyd3 rescues NMDAR and cognitive deficits in a mouse model of Alzheimer’s disease. It highlights the potential of epigenetic treatment in neurodegenerative diseases.
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影响因子：
25
作者：
Gan L;Cookson MR;Petrucelli L;La Spada AR
通讯作者：
La Spada AR
影响因子：
13.6
作者：
Cao Q;Wang W;Williams JB;Yang F;Wang ZJ;Yan Z
通讯作者：
Yan Z
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
4.2
作者：
Mastroeni D;Delvaux E;Nolz J;Tan Y;Grover A;Oddo S;Coleman PD
通讯作者：
Coleman PD