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SETD7-mediated monomethylation is enriched on soluble Tau in Alzheimer’s disease
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2021-07-02 , DOI: 10.1186/s13024-021-00468-x
Maria Bichmann 1 , Nuria Prat Oriol 1, 2 , Ebru Ercan-Herbst 1 , David C Schöndorf 1, 3 , Borja Gomez Ramos 1, 4, 5 , Vera Schwärzler 1 , Marie Neu 3 , Annabelle Schlüter 3 , Xue Wang 6 , Liang Jin 6 , Chenqi Hu 6 , Yu Tian 6 , Janina S Ried 7 , Per Haberkant 8 , Laura Gasparini 3 , Dagmar E Ehrnhoefer 1, 3
Affiliation  

Human tauopathies including Alzheimer’s disease (AD) are characterized by alterations in the post-translational modification (PTM) pattern of Tau, which parallel the formation of insoluble Tau aggregates, neuronal dysfunction and degeneration. While PTMs on aggregated Tau have been studied in detail, much less is known about the modification patterns of soluble Tau. Furthermore, PTMs other than phosphorylation have only come into focus recently and are still understudied. Soluble Tau species are likely responsible for the spreading of pathology during disease progression and are currently being investigated as targets for immunotherapies. A better understanding of their biochemical properties is thus of high importance. We used a mass spectrometry approach to characterize Tau PTMs on a detergent-soluble fraction of human AD and control brain tissue, which led to the discovery of novel lysine methylation events. We developed specific antibodies against Tau methylated at these sites and biochemically characterized methylated Tau species in extracts from human brain, the rTg4510 mouse model and in hiPSC-derived neurons. Our study demonstrates that methylated Tau levels increase with Tau pathology stage in human AD samples as well as in a mouse model of Tauopathy. Methylated Tau is enriched in soluble brain extracts and is not associated with hyperphosphorylated, high molecular weight Tau species. We also show that in hiPSC-derived neurons and mouse brain, methylated Tau preferentially localizes to the cell soma and nuclear fractions and is absent from neurites. Knock down and inhibitor studies supported by proteomics data led to the identification of SETD7 as a novel lysine methyltransferase for Tau. SETD7 specifically methylates Tau at K132, an event that facilitates subsequent methylation at K130. Our findings indicate that methylated Tau has a specific somatic and nuclear localization, suggesting that the methylation of soluble Tau species may provide a signal for their translocation to different subcellular compartments. Since the mislocalization and depletion of Tau from axons is associated with tauopathies, our findings may shed light onto this disease-associated phenomenon.

中文翻译:


阿尔茨海默病中 SETD7 介导的单甲基化在可溶性 Tau 上富集



包括阿尔茨海默病 (AD) 在内的人类 tau 蛋白病的特征是 Tau 翻译后修饰 (PTM) 模式的改变,这与不溶性 Tau 聚集体的形成、神经元功能障碍和变性同时发生。虽然对聚集 Tau 的 PTM 进行了详细研究,但对可溶性 Tau 的修饰模式知之甚少。此外,除磷酸化之外的 PTM 最近才引起人们的关注,并且尚未得到充分研究。可溶性 Tau 蛋白物种可能是疾病进展过程中病理学传播的原因,目前正在作为免疫疗法的靶点进行研究。因此,更好地了解它们的生化特性非常重要。我们使用质谱方法来表征人类 AD 的去垢剂可溶部分上的 Tau PTM,并控制脑组织,从而发现了新的赖氨酸甲基化事件。我们开发了针对这些位点甲基化 Tau 的特异性抗体,并对人脑、rTg4510 小鼠模型和 hiPSC 衍生神经元提取物中的甲基化 Tau 物种进行生化表征。我们的研究表明,在人类 AD 样本以及 Tau 病小鼠模型中,甲基化 Tau 水平随着 Tau 病理阶段的增加而增加。甲基化 Tau 蛋白富含可溶性脑提取物,并且与过度磷酸化的高分子量 Tau 蛋白物种无关。我们还表明,在 hiPSC 衍生的神经元和小鼠大脑中,甲基化 Tau 优先定位于细胞体和核部分,并且在神经突中不存在。蛋白质组学数据支持的敲低和抑制剂研究导致 SETD7 被鉴定为 Tau 的新型赖氨酸甲基转移酶。 SETD7 特异性地在 K132 位点甲基化 Tau,这一事件有利于随后在 K130 位点的甲基化。我们的研究结果表明,甲基化 Tau 具有特定的体细胞和核定位,这表明可溶性 Tau 物种的甲基化可能为其易位到不同的亚细胞区室提供信号。由于轴突中 Tau 蛋白的错误定位和消耗与 tau 蛋白病相关,因此我们的发现可能有助于揭示这种与疾病相关的现象。
更新日期:2021-07-04
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