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首页> 外文期刊>Biophysical Chemistry: An International Journal Devoted to the Physical Chemistry of Biological Phenomena >A model of amyloid's role in disease based on fibril fracture.
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A model of amyloid's role in disease based on fibril fracture.

机译：基于原纤维断裂的淀粉样蛋白在疾病中的作用模型。

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Although the correlative evidence relating the presence of amyloid fibrils and certain disease states (e.g. Alzheimer's disease and Type 2 Diabetes) is overwhelming, a direct causative role for amyloid has proved harder to establish. Current thinking links a narrow region of the aggregate protein size distribution, the so called 'early aggregate' domain to cellular toxicity. A troubling feature of this theory however is that the nucleated reaction mechanism by which amyloid formation is believed to occur results in a very low number concentration of early aggregates which are rapidly extended to form amyloid fibrils. This situation means that the concentration of early aggregates is very low at the time when they are supposedly at their most toxic. Here we adopt a novel explicit simulation strategy to examine a kinetic regime involving nucleated growth combined with fibril fragmentation under which this situation can be reversed so as to produce a high number concentration of small on-pathway toxic aggregates. Dependent upon the rate of fragmentation, the time scale for generation of toxic early aggregates may be coupled, uncoupled or disassociated from the time scale for the appearance of amyloid fibrils. Furthermore the model presents itself as a biochemical 'switch' transitioning between modes of amyloid induced cell death dependent upon either specific amyloid toxicity or non-specific solid mass induced tissue damage.
机译：尽管有关淀粉样蛋白原纤维的存在与某些疾病状态（例如阿尔茨海默氏病和2型糖尿病）的相关证据不胜枚举，但事实证明，淀粉样蛋白的直接致病作用难以确立。目前的想法将聚集蛋白大小分布的狭窄区域（即所谓的“早期聚集”结构域）与细胞毒性联系在一起。然而，该理论的令人不安的特征是，据信发生淀粉样蛋白形成的成核反应机理导致非常低浓度的早期聚集体迅速聚集形成淀粉样蛋白原纤维。这种情况意味着早期聚集体的浓度在毒性最强的时候非常低。在这里，我们采用一种新颖的显式模拟策略，以检查涉及成核生长和原纤维断裂的动力学机制，在这种机制下，这种情况可以逆转，从而产生大量浓度的小途中有毒聚集体。取决于碎裂的速率，可以将产生有毒早期聚集体的时间尺度与淀粉样蛋白原纤维出现的时间尺度相耦合，分离或分离。此外，该模型将自身呈现为取决于特异性淀粉样蛋白毒性或非特异性固体物质诱导的组织损伤的淀粉样蛋白诱导的细胞死亡模式之间的生化“转换”转变。

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