Can the lack of fibrillar form of alpha-synuclein in Lewy bodies be explained by its catalytic activity?

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., Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes, Nature Neuroscience 22 (2019) 1099–1109) 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）的致病病理生理机制对于开发治疗干预措施至关重要。直到最近，人们还认为路易小体（LBs）——帕金森病的标志性特征，主要由α - 突触核蛋白（α - syn）纤维组成。近期的研究结果（Shahmoradian等人，《帕金森病中的路易病理包含密集的细胞器和脂质膜》，《自然神经科学》22卷（2019年）1099 - 1109页）表明，路易小体中缺乏α - syn的纤维形式。在此，我们提出这一令人惊讶的观察结果可以用α - syn纤维形式的催化活性来解释。我们假设α - syn纤维催化路易小体的形成，但并不成为其一部分。我们基于这一假设建立了一个数学模型。通过使用所建立的模型，我们研究了这一假设的结果。特别是，该模型表明，帕金森病的长潜伏期可以通过导致其发展的两步聚集过程来解释：（i）单体α - syn聚集成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，进而导致神经元饥饿和死亡。该模型显示，降低体细胞溶酶体中α - syn聚集体的破坏速率会加速路易小体的形成。该模型的另一个结果是预测，在膜结合细胞器聚集成路易小体已经开始后，从大脑中清除α - syn聚集体可能无法阻止帕金森病的进展，因为路易小体的形成是一个自催化过程；因此，即使在没有α - syn聚集体的情况下，膜结合细胞器的聚集体也会催化路易小体的形成。所进行的敏感性研究使得建立模型参数对胞体中囊泡聚集体形成的影响的层级关系成为可能。