Scale-free neurodegeneration: cellular heterogeneity and the stretched exponential kinetics of cell death
Scale-free neurodegeneration: cellular heterogeneity and the stretched exponential kinetics of cell death
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DOI：
10.1016/j.jtbi.2004.10.028
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发表时间：
2005-04-21
影响因子：
2
通讯作者：
Lumsden, CJ
中科院分区：
文献类型：
--
作者：
Clarke, G;Lumsden, CJ
神经退行性疾病是一组潜伏性疾病，其特征是严重的身体和认知影响，通常对受影响的个人及其家庭的生活产生破坏性后果。这些疾病中很大一部分的一个共同特征是受影响的神经元致力于经历一种称为程序性细胞死亡或凋亡的活性形式的变性。虽然在过去的几年里，我们对神经退行性变的分子事件的理解有了显著的提高，但我们对决定神经元磨损时间模式的细胞和组织特性的了解是有限的。我们最近证明了各种疾病中的神经退行性动力学很好地符合指数衰减函数，并提出了一种通用的一击开关机制，其中突变和受损的神经元以活性状态存在，其特征在于引发细胞凋亡的风险增加但恒定（Nature，406，第195页）。在这里，我们表明，一个重尾拉伸指数函数能够更好地解释神经退行性动力学数据。此外，所有可用的数据，根据其相应的最佳拟合拉伸指数参数的归一化表明，广义模型是一致的神经元细胞死亡的普遍机制，大大提高了恒定风险模型。与所有细胞都表现出相同的启动凋亡风险的原始模型相反，拉伸指数模型与每个神经元经历的恒定风险是一致的，该风险不同于退化群体中其他细胞所经历的风险，这可能是由于细胞微环境的空间差异。有趣的是，预测的整个细胞群的风险分布可以通过幂律函数拟合，进一步表明退化神经元组织的无标度特性可能作为神经组织中细胞死亡动力学的有效调节剂。(c)2004爱思唯尔有限公司保留所有权利。
Neurodegenerative disorders are an insidious group of diseases characterized by severe physical and cognitive effects that often have devastating consequences for the lives of affected individuals and their families. One feature common to a significant proportion of these diseases is that affected neurons commit to undergoing an active form of degeneration known as programmed cell death, or apoptosis. Although intense effort over the past several years has resulted is a remarkable increase in our understanding of the molecular events involved in neurodegeneration, our knowledge regarding the cellular and tissue properties that determine the temporal patterns of neuronal attrition is limited. We recently demonstrated that neurodegenerative kinetics in various diseases fit well to exponential decay functions, and proposed a universal one-hit switch mechanism in which mutant and injured neurons exist in a viable state characterized by an increased but constant risk of initiating apoptosis (Nature, 406, p. 195). Here we show that a heavy-tailed stretched exponential function is better able to account for neurodegenerative kinetic data. Moreover, normalization of all available data according to their corresponding best-fit stretched exponential parameters suggest that the generalized model is consistent with a universal mechanism of neuronal cell death that is greatly improved over the constant risk model. In contrast to the original model in which all cells exhibit an identical risk of initiating apoptosis, the stretched exponential model is consistent with each neuron experiencing a constant risk that is different from that experienced by other cells in the degenerating population, perhaps due to spatial differences in the cellular microenvironment. Intriguingly, the predicted distribution of risk across the cell population can be fit by a power-law function, further suggesting that scale-free properties of degenerating neuronal tissues might act as potent regulators of the kinetics of cell death in neural tissue. (c) 2004 Elsevier Ltd. All rights reserved.