Rieger Theodore R, Morimoto Richard I, Hatzimanikatis Vassily
Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, USA.
Biophys J. 2006 Feb 1;90(3):886-95. doi: 10.1529/biophysj.105.066662. Epub 2005 Nov 18.
Neurodegenerative disease can originate from the misfolding and aggregation of proteins, such as Amyloid-beta, SOD1, or Huntingtin. Fortunately, all cells possess protein quality control machinery that sequesters misfolded proteins, either refolding or degrading them, before they can self-associate into proteotoxic oligomers and aggregates. This activity is largely performed by the stress response chaperones (i.e., Hsp70). However, the expression level of molecular chaperones varies widely among cell types. To understand the potential consequence of this variation, we studied the process of protein aggregation in the presence of molecular chaperones using mathematical modeling. We demonstrate that protein aggregation, in the presence of molecular chaperones, is a bistable process. Bistability in protein aggregation offers an explanation for threshold transitions to high aggregate concentration, which are observed both in vitro and in vivo. Additionally, we show that slight variations in chaperone concentration, due to natural fluctuations, have important consequences in a bistable system for the onset of protein aggregation. Therefore, our results offer a possible theoretical explanation for neuronal vulnerability observed in vivo and the onset of neurodegenerative phenotypes in neurons lacking an effective heat-shock response.
神经退行性疾病可能源于蛋白质的错误折叠和聚集，如β-淀粉样蛋白、超氧化物歧化酶1（SOD1）或亨廷顿蛋白。幸运的是，所有细胞都拥有蛋白质质量控制机制，该机制在错误折叠的蛋白质能够自组装成具有蛋白毒性的寡聚体和聚集体之前，将其隔离，要么使其重新折叠，要么将其降解。这项活动主要由应激反应伴侣蛋白（即热休克蛋白70，Hsp70）来执行。然而，分子伴侣蛋白的表达水平在不同细胞类型中差异很大。为了了解这种差异的潜在后果，我们使用数学建模研究了在分子伴侣蛋白存在的情况下蛋白质聚集的过程。我们证明，在分子伴侣蛋白存在的情况下，蛋白质聚集是一个双稳态过程。蛋白质聚集的双稳态为向高聚集体浓度的阈值转变提供了解释，这种转变在体外和体内都能观察到。此外，我们表明，由于自然波动导致的伴侣蛋白浓度的轻微变化，在双稳态系统中对蛋白质聚集的起始具有重要影响。因此，我们的结果为体内观察到的神经元易损性以及缺乏有效热休克反应的神经元中神经退行性表型的起始提供了一种可能的理论解释。
