Montanino Annaclaudia, Saeedimasine Marzieh, Villa Alessandra, Kleiven Svein
Division of Neuronic Engineering, Royal Institute of Technology (KTH), Stockholm, Sweden.
Department of Biosciences and Nutrition, Karolinska Institutet (KI), Stockholm, Sweden.
Front Neurol. 2020 Jan 30;11:25. doi: 10.3389/fneur.2020.00025. eCollection 2020.
Traumatic brain injuries are a leading cause of morbidity and mortality worldwide. With almost 50% of traumatic brain injuries being related to axonal damage, understanding the nature of cellular level impairment is crucial. Experimental observations have so far led to the formulation of conflicting theories regarding the cellular primary injury mechanism. Disruption of the axolemma, or alternatively cytoskeletal damage has been suggested mainly as injury trigger. However, mechanoporation thresholds of generic membranes seem not to overlap with the axonal injury deformation range and microtubules appear too stiff and too weakly connected to undergo mechanical breaking. Here, we aim to shed a light on the mechanism of primary axonal injury, bridging finite element and molecular dynamics simulations. Despite the necessary level of approximation, our models can accurately describe the mechanical behavior of the unmyelinated axon and its membrane. More importantly, they give access to quantities that would be inaccessible with an experimental approach. We show that in a typical injury scenario, the axonal cortex sustains deformations large enough to entail pore formation in the adjoining lipid bilayer. The observed axonal deformation of 10-12% agree well with the thresholds proposed in the literature for axonal injury and, above all, allow us to provide quantitative evidences that do not exclude pore formation in the membrane as a result of trauma. Our findings bring to an increased knowledge of axonal injury mechanism that will have positive implications for the prevention and treatment of brain injuries.
创伤性脑损伤是全球发病和死亡的主要原因。几乎50%的创伤性脑损伤与轴突损伤有关，因此了解细胞水平损伤的本质至关重要。迄今为止，实验观察结果导致了关于细胞原发性损伤机制的相互矛盾的理论的形成。轴膜破裂或细胞骨架损伤主要被认为是损伤触发因素。然而，普通膜的机械穿孔阈值似乎与轴突损伤变形范围不重叠，并且微管似乎过于僵硬且连接薄弱，无法承受机械断裂。在这里，我们旨在通过结合有限元模拟和分子动力学模拟来阐明原发性轴突损伤的机制。尽管存在必要的近似程度，但我们的模型可以准确描述无髓鞘轴突及其膜的力学行为。更重要的是，它们能够获取实验方法无法获得的量。我们表明，在典型的损伤情况下，轴突皮层承受的变形足够大，足以导致相邻脂质双层中形成孔隙。观察到的10%-12%的轴突变形与文献中提出的轴突损伤阈值非常吻合，最重要的是，使我们能够提供定量证据，并不排除创伤导致膜中形成孔隙。我们的研究结果增加了对轴突损伤机制的认识，这将对脑损伤的预防和治疗产生积极影响。
