Fornara Basile, Igel Angélique, Béringue Vincent, Martin Davy, Sibille Pierre, Pujo-Menjouet Laurent, Rezaei Human
Université Paris-Saclay, INRAe, UVSQ, VIM, 78350 Jouy-en-Josas, France.
Université Claude Bernard Lyon 1, ICJ UMR5208, CNRS, Ecole Centrale de Lyon, INSA Lyon, Université Jean Monnet, Inria Dracula, 69622 Villeurbanne, France.
iScience. 2024 Nov 13;27(12):111381. doi: 10.1016/j.isci.2024.111381. eCollection 2024 Dec 20.
Prion diseases, or transmissible spongiform encephalopathies (TSEs), are neurodegenerative disorders caused by the accumulation of misfolded conformers (PrP) of the cellular prion protein (PrP). During the pathogenesis, the PrP seeds disseminate in the central nervous system and convert PrP leading to the formation of insoluble assemblies. As for conventional infectious diseases, variations in the clinical manifestation define a specific prion strain which correspond to different PrP structures. In this work, we implemented the recent developments on PrP structural diversity and tissue response to prion replication into a stochastic reaction-diffusion model using an application of the Gillespie algorithm. We showed that this combination of non-linearities can lead prion propagation to behave as a complex system, providing an alternative to the current paradigm to explain strain-specific phenotypes, tissue tropisms, and strain co-propagation while also clarifying the role of the connectome in the neuro-invasion process.
朊病毒疾病，即传染性海绵状脑病（TSEs），是由细胞朊蛋白（PrP）错误折叠的构象异构体（PrP）积累引起的神经退行性疾病。在发病过程中，PrP种子在中枢神经系统中传播并转化PrP，导致不溶性聚集体的形成。对于传统传染病而言，临床表现的差异定义了特定的朊病毒株，其对应于不同的PrP结构。在这项工作中，我们利用 Gillespie 算法的应用，将 PrP 结构多样性和组织对朊病毒复制的反应的最新进展纳入一个随机反应扩散模型。我们表明，这种非线性的组合可以使朊病毒传播表现为一个复杂系统，为当前解释毒株特异性表型、组织嗜性和毒株共同传播的范式提供了一种替代方案，同时也阐明了连接组在神经侵袭过程中的作用。
