Protein phosphorylation in neurodegeneration: friend or foe?
Protein phosphorylation in neurodegeneration: friend or foe?
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DOI：
10.3389/fnmol.2014.00042
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发表时间：
2014
影响因子：
4.8
通讯作者：
Outeiro TF
中科院分区：
文献类型：
--
作者：
Tenreiro S;Eckermann K;Outeiro TF
蛋白质错误折叠和聚集是神经退行性疾病（包括阿尔茨海默病（AD）、帕金森病（PD）和额颞叶痴呆（FTD））中的常见标志。在这些疾病中，特定蛋白质的错误折叠和聚集与神经元变性一起发生在某些特定的脑区域，这取决于疾病和疾病的阶段。然而，我们仍然不完全了解蛋白质聚集的机制，以及这是否构成保护性或有害的过程。在PD中，α-突触核蛋白（aSyn）形成蛋白质聚集体，称为路易体，并在丝氨酸129处磷酸化。其他残基也被证明是磷酸化的，但磷酸化在蛋白质的生物学和病理生理学中的意义仍然存在争议。在AD和FTD中，tau蛋白的过度磷酸化导致其错误折叠和聚集。同样，我们对tau蛋白磷酸化在该蛋白的生物学和病理生理学中的确切后果的理解仍然有限。通过使用各种模式生物和技术方法，我们现在对磷酸化在这些蛋白质行为中的作用有了更深入的了解。在这篇综述中，我们涵盖了该领域的最新研究结果，并讨论了如何靶向磷酸化事件可能被用于这些破坏性神经系统疾病的治疗干预。
Protein misfolding and aggregation is a common hallmark in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and fronto-temporal dementia (FTD). In these disorders, the misfolding and aggregation of specific proteins occurs alongside neuronal degeneration in somewhat specific brain areas, depending on the disorder and the stage of the disease. However, we still do not fully understand the mechanisms governing protein aggregation, and whether this constitutes a protective or detrimental process. In PD, alpha-synuclein (aSyn) forms protein aggregates, known as Lewy bodies, and is phosphorylated at serine 129. Other residues have also been shown to be phosphorylated, but the significance of phosphorylation in the biology and pathophysiology of the protein is still controversial. In AD and in FTD, hyperphosphorylation of tau protein causes its misfolding and aggregation. Again, our understanding of the precise consequences of tau phosphorylation in the biology and pathophysiology of the protein is still limited. Through the use of a variety of model organisms and technical approaches, we are now gaining stronger insight into the effects of phosphorylation in the behavior of these proteins. In this review, we cover recent findings in the field and discuss how targeting phosphorylation events might be used for therapeutic intervention in these devastating diseases of the nervous system.
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