A physics-based model explains the prion-like features of neurodegeneration in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis
A physics-based model explains the prion-like features of neurodegeneration in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis
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DOI：
10.1016/j.jmps.2018.10.013
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发表时间：
2019-03
影响因子：
5.3
通讯作者：
J. Weickenmeier;M. Jucker;A. Goriely;E. Kuhl
中科院分区：
文献类型：
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作者：
J. Weickenmeier;M. Jucker;A. Goriely;E. Kuhl
朊病毒病的特征是一种连锁反应，其中感染性错误折叠蛋白质迫使天然蛋白质形成类似的致病结构。最近的研究加强了这样一个假设，即朊病毒模式错误折叠蛋白质的模板化生长和扩散可以帮助解释各种神经退行性疾病的进展。然而，我们目前对朊病毒样生长和传播的理解是相当经验的。在这里，我们表明，一个基于物理学的反应扩散模型可以解释的生长和扩散的错误折叠的蛋白质在阿尔茨海默氏症，帕金森氏症和肌萎缩侧索硬化症。为了表征错误折叠蛋白质在整个大脑中的进展，我们将经典的Fisher-Kolmogorov方程与各向异性扩散模型相结合，模拟了整个矢状面和整个大脑的错误折叠。在一个系统的敏感性分析中，我们探索的作用，个别模型参数，并表明，错误折叠的蛋白质浓度是敏感的生长，细胞外扩散，轴突运输的系数，轴突纤维的方向，并初始播种区域。我们的模型正确预测了阿尔茨海默病中的淀粉样蛋白-β沉积物和tau包涵体，帕金森病中的α-突触核蛋白包涵体，以及肌萎缩侧索硬化症中的TDP-43包涵体，并与患病人脑的组织学模式表现出极好的一致性。当在整个大脑中整合时，我们的浓度分布导致生物标志物曲线显示出与临床生物标志物模型的S形形状和定性时间轴惊人的相似性。我们的研究结果表明，在各种神经退行性疾病中的错误折叠蛋白质的生长和传播遵循一个普遍的规律，遵循非线性反应和各向异性扩散的基本物理原理。我们的研究结果证实了一个共同的基本原则的发病机制的各种神经退行性疾病的概念，朊病毒的范例。对错误折叠的淀粉样蛋白-β、tau、α-突触核蛋白和TDP-43的生长和扩散的更定量的理解将使我们能够建立疾病进展的预后时间表。这可能具有重要的临床意义，从更准确地估计神经退行性疾病的社会经济负担到更明智的临床试验和药物干预设计。
Prion disease is characterized by a chain reaction in which infectious misfolded proteins force native proteins into a similar pathogenic structure. Recent studies have reinforced the hypothesis that the prion paradigm–the templated growth and spreading of misfolded proteins–could help explain the progression of a variety of neurodegenerative disorders. However, our current understanding of prion-like growth and spreading is rather empirical. Here we show that a physics-based reaction-diffusion model can explain the growth and spreading of misfolded protein in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. To characterize the progression of misfolded proteins across the brain, we combine the classical Fisher–Kolmogorov equation for population dynamics with an anisotropic diffusion model and simulate misfolding across a sagittal section and across the entire brain. In a systematic sensitivity analysis, we probe the role of the individual model parameters and show that the misfolded protein concentration is sensitive to the coefficients of growth, extracellular diffusion, and axonal transport, to the axonal fiber orientation, and to the initial seeding region. Our model correctly predicts amyloid-βdeposits and tau inclusions in Alzheimer’s disease,α-synuclein inclusions in Parkinson’s disease, and TDP-43 inclusions in amyotrophic lateral sclerosis and displays excellent agreement with the histological patterns in diseased human brains. When integrated across the brain, our concentration profiles result in biomarker curves that display a striking similarity with the sigmoid shape and qualitative timeline of clinical biomarker models. Our results suggest that misfolded proteins in various neurodegenerative disorders grow and spread according to a universal law that follows the basic physical principles of nonlinear reaction and anisotropic diffusion. Our findings substantiate the notion of a common underlying principle for the pathogenesis of a wide variety of neurodegenerative disorders, the prion paradigm. A more quantitative understanding of the growth and spreading of misfolded amyloid-β, tau,α-synuclein, and TDP-43 would allow us to establish a prognostic timeframe of disease progression. This could have important clinical implications, ranging from more accurate estimates of the socioeconomic burden of neurodegeneration to a more informed design of clinical trials and pharmacological intervention.