Institut für Zellbiologie, Universität Bayreuth Bayreuth, Germany.
Front Mol Neurosci. 2015 Mar 12;8:8. doi: 10.3389/fnmol.2015.00008. eCollection 2015.
Critically impaired protein degradation is discussed to contribute to neurodegenerative disorders, including Parkinson's, Huntington's, Alzheimer's, and motor neuron diseases. Misfolded, aggregated, or surplus proteins are efficiently degraded via distinct protein degradation pathways, including the ubiquitin-proteasome system, autophagy, and vesicular trafficking. These pathways are regulated by covalent modification of target proteins with the small protein ubiquitin and are evolutionary highly conserved from humans to yeast. The yeast Saccharomyces cerevisiae is an established model for deciphering mechanisms of protein degradation, and for the elucidation of pathways underlying programmed cell death. The expression of human neurotoxic proteins triggers cell death in yeast, with neurotoxic protein-specific differences. Therefore, yeast cell death models are suitable for analyzing the role of protein degradation pathways in modulating cell death upon expression of disease-causing proteins. This review summarizes which protein degradation pathways are affected in these yeast models, and how they are involved in the execution of cell death. I will discuss to which extent this mimics the situation in other neurotoxic models, and how this may contribute to a better understanding of human disorders.
严重受损的蛋白质降解被认为是导致神经退行性疾病的原因之一，包括帕金森病、亨廷顿病、阿尔茨海默病和运动神经元疾病。错误折叠、聚集或过剩的蛋白质可以通过不同的蛋白质降解途径有效降解，包括泛素-蛋白酶体系统、自噬和囊泡运输。这些途径受目标蛋白与小分子蛋白泛素的共价修饰调节，从人类到酵母都具有高度的进化保守性。酵母酿酒酵母是解析蛋白质降解机制和阐明程序性细胞死亡相关途径的成熟模型。人类神经毒性蛋白的表达会引发酵母细胞死亡，具有神经毒性蛋白特异性差异。因此，酵母细胞死亡模型适合分析在表达致病蛋白时蛋白质降解途径在调节细胞死亡中的作用。这篇综述总结了这些酵母模型中受影响的蛋白质降解途径，以及它们如何参与细胞死亡的执行。我将讨论这种情况在其他神经毒性模型中的程度，以及这如何有助于更好地理解人类疾病。
