Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Mechanical and Aerospace Engineering, North Carolina State University, Raleigh, NC 27695-7910, USA.
Math Biosci. 2022 Feb;344:108754. doi: 10.1016/j.mbs.2021.108754. Epub 2021 Dec 7.
Finding the causative pathophysiological mechanisms for Parkinson's disease (PD) is important for developing therapeutic interventions. Until recently, it was believed that Lewy bodies (LBs), the hallmark of PD, are mostly composed of alpha-synuclein (α-syn) fibrils. Recent results (Shahmoradian et al. (2019)) demonstrated that the fibrillar form of α-syn is lacking from LBs. Here we propose that this surprising observation can be explained by the catalytic activity of the fibrillar form of α-syn. We assumed that α-syn fibrils catalyze the formation of LBs, but do not become part of them. We developed a mathematical model based on this hypothesis. By using the developed model, we investigated the consequences of this hypothesis. In particular, the model suggests that the long incubation time of PD can be explained by a two-step aggregation process that leads to its development: (i) aggregation of monomeric α-syn into α-syn oligomers and fibrils and (ii) clustering of membrane-bound organelles, which may cause disruption of axonal trafficking and lead to neuron starvation and death. The model shows that decreasing the rate of destruction of α-syn aggregates in somatic lysosomes accelerates the formation of LBs. Another consequence of the model is the prediction that removing α-syn aggregates from the brain after the aggregation of membrane-bound organelles into LBs has started may not stop the progression of PD because LB formation is an autocatalytic process; hence, the formation of LBs will be catalyzed by aggregates of membrane-bound organelles even in the absence of α-syn aggregates. The performed sensitivity study made it possible to establish the hierarchy of model parameters with respect to their effect on the formation of vesicle aggregates in the soma.
寻找帕金森病（PD）的因果病理生理机制对于开发治疗干预措施非常重要。直到最近，人们还认为路易体（LB）是 PD 的主要特征，它主要由α-突触核蛋白（α-syn）纤维组成。最近的研究结果（Shahmoradian 等人，2019 年）表明，LB 中缺乏α-syn 的纤维形式。在这里，我们提出这个惊人的观察结果可以用α-syn 的纤维形式的催化活性来解释。我们假设α-syn 纤维可以催化 LB 的形成，但不会成为其组成部分。我们基于这个假设开发了一个数学模型。通过使用所开发的模型，我们研究了这个假设的后果。特别是，该模型表明，PD 的长潜伏期可以通过导致其发展的两步聚合过程来解释：（i）单体α-syn 聚合形成α-syn 寡聚体和纤维，以及（ii）膜结合细胞器的聚集，这可能导致轴突运输中断，并导致神经元饥饿和死亡。该模型表明，降低溶酶体中α-syn 聚集体的破坏速度可以加速 LB 的形成。该模型的另一个结果是，预测在膜结合细胞器聚集到 LB 后，从大脑中去除α-syn 聚集体可能不会阻止 PD 的进展，因为 LB 的形成是一个自催化过程；因此，即使没有α-syn 聚集体，LB 的形成也将由膜结合细胞器的聚集体催化。进行的敏感性研究使我们能够确定模型参数对体细胞中囊泡聚集体形成的影响的层次结构。
