Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland; Bionanopark Ltd., Lodz, Poland.
Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
Ageing Res Rev. 2018 Dec;48:21-31. doi: 10.1016/j.arr.2018.09.003. Epub 2018 Sep 22.
A number of independent studies have shown the contribution of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the pathogenesis of several neurodegenerative disorders. Indeed, GAPDH aggregates have been found in many post-mortem samples of brains of patients diagnosed with Alzheimer's and Parkinson disease. Currently, it is accepted that GAPDH-mediated cell death pathways in the neurodegenerative processes are associated with apoptosis caused by GAPDH nuclear translocation and excessive aggregation under oxidative stress conditions. Also the role of GAPDH in neurodegenerative diseases is linked to it directly binding to specific amyloidogenic proteins and petides such as β-amyloid precursor protein, β-amyloid peptide and tau protein in Alzheimer's disease, huntingtin in Huntington's disease and α-synuclein in Parkinson disease. One of the latest studies indicated that GAPDH aggregates significantly accelerate amyloidogenesis of the β-amyloid peptide, which implies that aggregates of GAPDH may act as a specific aggregation "seed" in vitro. Previous detailed studies revealed that the active-site cysteine (Cys152) of GAPDH plays an essential role in the oxidative stress-induced aggregation of GAPDH associated with cell death. Furthermore, oxidative modification of this cysteine residue initiates the translocation of the enzyme to the nucleus, subsequently leading to apoptosis. The crystallographic structure of GAPDH shows that the Cys152 residue is located close to the surface of the molecule in a hydrophilic environment, which means that it can react with low molecular weight compounds such as hydroxynonenal or piceatannol. Therefore, it is highly possible that GAPDH may serve as a target for small molecule compounds with the potential to slow down or prevent the progression of neurodegenerative disorders. Recently appearing new evidence has highlighted the significance of low molecular weight compounds in counteracting the oxidation of GAPDH and consequently its aggregation and other unfavourable pathological processes. Hence, this review aims to present all recent findings concerning molecules that are able to interact with GAPDH and counteract its aggregation and translocation to the nucleus.
已有多项独立研究表明，甘油醛-3-磷酸脱氢酶（GAPDH）在多种神经退行性疾病的发病机制中具有重要作用。事实上，在许多被诊断为阿尔茨海默病和帕金森病的患者的大脑死后样本中，已经发现了 GAPDH 聚集体。目前，人们普遍认为，在神经退行性过程中，GAPDH 介导的细胞死亡途径与 GAPDH 核转位引起的细胞凋亡以及氧化应激条件下过度聚集有关。此外，GAPDH 在神经退行性疾病中的作用还与其直接与特定淀粉样蛋白原纤维蛋白和肽结合有关，如阿尔茨海默病中的β-淀粉样前体蛋白、β-淀粉样肽和 tau 蛋白，亨廷顿病中的亨廷顿蛋白和帕金森病中的α-突触核蛋白。最近的一项研究表明，GAPDH 聚集体可显著加速β-淀粉样肽的淀粉样生成，这意味着 GAPDH 聚集体可能在体外作为特定的聚集“种子”发挥作用。先前的详细研究表明，GAPDH 的活性位点半胱氨酸（Cys152）在与细胞死亡相关的氧化应激诱导的 GAPDH 聚集中发挥着重要作用。此外，该半胱氨酸残基的氧化修饰启动了酶向核内的易位，随后导致细胞凋亡。GAPDH 的晶体结构表明，Cys152 残基位于分子表面的亲水环境中，这意味着它可以与低分子量化合物如 4-羟基壬烯醛或白皮杉醇反应。因此，GAPDH 很可能成为具有减缓或阻止神经退行性疾病进展潜力的小分子化合物的靶标。最近出现的新证据强调了低分子量化合物在对抗 GAPDH 氧化及其聚集和其他不利病理过程中的重要性。因此，本综述旨在介绍所有关于能够与 GAPDH 相互作用并拮抗其聚集和核易位的分子的最新发现。
