Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
FEBS Lett. 2013 Apr 17;587(8):1139-46. doi: 10.1016/j.febslet.2013.02.043. Epub 2013 Mar 1.
Protein misfolding and proteostasis decline is a common feature of many neurodegenerative diseases. However, modeling the complexity of proteostasis and the global cellular consequences of its disruption is a challenge, particularly in live neurons. Although conventional approaches, based on population measures and single "snapshots", can identify cellular changes during neurodegeneration, they fail to determine if these cellular events drive cell death or act as adaptive responses. Alternatively, a "systems" cell biology approach known as longitudinal survival analysis enables single neurons to be followed over the course of neurodegeneration. By capturing the dynamics of misfolded proteins and the multiple cellular events that occur along the way, the relationship of these events to each other and their importance and role during cell death can be determined. Quantitative models of proteostasis dysfunction may yield unique insight and novel therapeutic strategies for neurodegenerative disease.
蛋白质错误折叠和蛋白质稳态下降是许多神经退行性疾病的共同特征。然而，模拟蛋白质稳态的复杂性及其破坏对全局细胞的影响是一个挑战，特别是在活神经元中。尽管基于群体测量和单个“快照”的传统方法可以在神经退行性变过程中识别细胞变化，但它们无法确定这些细胞事件是导致细胞死亡还是作为适应性反应。相反，一种称为纵向生存分析的“系统”细胞生物学方法可以使单个神经元在神经退行性变过程中被跟踪。通过捕获错误折叠蛋白的动态以及沿着这条通路发生的多种细胞事件，可以确定这些事件之间的关系及其在细胞死亡过程中的重要性和作用。蛋白质稳态功能障碍的定量模型可能为神经退行性疾病提供独特的见解和新的治疗策略。
