Neurodegenerative diseases like Alzheimer’s, Parkinson’s and Huntington’s disease involves abnormal aggregation and accumulation of toxic proteins aggregates. Post-translational modifications (PTMs) of the causative proteins play an important role in the etiology of disease as they could either slow down or accelerate the disease progression. Alzheimer disease is associated with the aggregation and accumulation of two major protein aggregates—intracellular neurofibrillary tangles made up of microtubule-associated protein Tau and extracellular Amyloid-β plaques. Post-translational modifications are important for the regulation of Tau`s function but an imbalance in PTMs may lead to abnormal Tau function and aggregation. Tau methylation is one of the important PTM of Tau in its physiological state. However, the methylation signature on Tau lysine changes once it acquires pathological aggregated form. Tau methylation can compete with other PTMs such as acetylation and ubiquitination. The state of PTM at these sites determines the fate of Tau protein in terms of its function and stability. The global methylation in neurons, microglia and astrocytes are involved in multiple cellular functions involving their role in epigenetic regulation of gene expression via DNA methylation. Here, we have discussed the effect of methylation on Tau function in a site-specific manner and their cross-talk with other lysine modifications. We have also elaborated the role of methylation in epigenetic aspects and neurodegenerative conditions associated with the imbalance in methylation metabolism affecting global methylation state of cells.

中文翻译：

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甲基化是阿尔茨海默氏病 Tau 聚集和神经元健康的关键调节因子

阿尔茨海默氏症、帕金森氏症和亨廷顿舞蹈症等神经退行性疾病涉及有毒蛋白质聚集体的异常聚集和积累。致病蛋白的翻译后修饰 (PTM) 在疾病病因学中发挥着重要作用，因为它们可以减缓或加速疾病进展。阿尔茨海默病与两种主要蛋白质聚集体的聚集和积累有关——由微管相关蛋白 Tau 组成的细胞内神经原纤维缠结和细胞外淀粉样蛋白-β 斑块。翻译后修饰对于 Tau 功能的调节很重要，但 PTM 的不平衡可能会导致 Tau 功能和聚集异常。Tau 甲基化是 Tau 生理状态下重要的 PTM 之一。然而，一旦 Tau 赖氨酸获得病理性聚集形式，其甲基化特征就会发生变化。Tau 甲基化可以与其他 PTM 竞争，例如乙酰化和泛素化。这些位点的 PTM 状态决定了 Tau 蛋白的功能和稳定性的命运。神经元、小胶质细胞和星形胶质细胞中的整体甲基化参与多种细胞功能，涉及它们通过 DNA 甲基化在基因表达的表观遗传调控中的作用。在这里，我们讨论了甲基化以位点特异性方式对 Tau 功能的影响以及它们与其他赖氨酸修饰的串扰。我们还阐述了甲基化在表观遗传方面和与影响细胞整体甲基化状态的甲基化代谢失衡相关的神经退行性疾病中的作用。