Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases.
Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases.
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DOI：
10.1016/j.jbc.2023.105411
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发表时间：
2023-12
影响因子：
4.8
通讯作者：
Vocadlo, David J.
中科院分区：
文献类型：
--
作者：
Pratt, Matthew R.;Vocadlo, David J.
O-GlcNAc 是核蛋白和细胞质蛋白上常见的修饰。确定从蛋白质中去除 O-GlcNAc 的酶 O-GlcNAcase (OGA) 的催化机制，能够创建这种调节酶的有效和选择性抑制剂。此类抑制剂已成为帮助揭示这种修饰的细胞和有机体生理作用的重要工具。此外，OGA 抑制剂对于将 O-GlcNAc 的增强定义为一种有前景的疾病缓解方法来对抗包括阿尔茨海默病和帕金森病在内的多种神经退行性疾病非常重要。这些研究促进了 OGA 抑制剂的临床应用的开发和优化。这些化合物在早期临床研究中已被证明具有良好的耐受性，并正在稳步推进临床。尽管取得了这些进展，O-GlcNAc 预防这些不同类型的神经变性的机制仍然是人们持续关注的话题，因为洞察力的提高可能有助于创建更有针对性的策略来调节 O-GlcNAc 以获得治疗益处。已发现 O-GlcNAc 发挥有益作用的相关途径包括自噬、坏死性凋亡和淀粉样前体蛋白的加工。最近，能够合成同质蛋白质的化学方法的开发和应用阐明了 O-GlcNAc 对蛋白质聚集的生化作用，并揭示了 O-GlcNAc 在热休克反应中的新作用。在这里，我们讨论了 O-GlcNAc 在神经退行性疾病中的特征、抑制剂在识别这种修饰作用中的应用，以及 O-GlcNAc 对神经退行性疾病相关蛋白质和通路的生化作用。
O-GlcNAc is a common modification found on nuclear and cytoplasmic proteins. Determining the catalytic mechanism of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, enabled the creation of potent and selective inhibitors of this regulatory enzyme. Such inhibitors have served as important tools in helping to uncover the cellular and organismal physiological roles of this modification. In addition, OGA inhibitors have been important for defining the augmentation of O-GlcNAc as a promising disease-modifying approach to combat several neurodegenerative diseases including both Alzheimer’s disease and Parkinson’s disease. These studies have led to development and optimization of OGA inhibitors for clinical application. These compounds have been shown to be well tolerated in early clinical studies and are steadily advancing into the clinic. Despite these advances, the mechanisms by which O-GlcNAc protects against these various types of neurodegeneration are a topic of continuing interest since improved insight may enable the creation of more targeted strategies to modulate O-GlcNAc for therapeutic benefit. Relevant pathways on which O-GlcNAc has been found to exert beneficial effects include autophagy, necroptosis, and processing of the amyloid precursor protein. More recently, the development and application of chemical methods enabling the synthesis of homogenous proteins have clarified the biochemical effects of O-GlcNAc on protein aggregation and uncovered new roles for O-GlcNAc in heat shock response. Here, we discuss the features of O-GlcNAc in neurodegenerative diseases, the application of inhibitors to identify the roles of this modification, and the biochemical effects of O-GlcNAc on proteins and pathways associated with neurodegeneration.
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DOI：
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发表时间：
2021-07-30
期刊：
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影响因子：
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通讯作者：
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影响因子：
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发表时间：
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影响因子：
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影响因子：
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