Emergence of directional bias in tau deposition from axonal transport dynamics.
Emergence of directional bias in tau deposition from axonal transport dynamics.
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DOI：
10.1371/journal.pcbi.1009258
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发表时间：
2021-07
影响因子：
4.3
通讯作者：
Raj A
中科院分区：
文献类型：
--
作者：
Torok J;Maia PD;Verma P;Mezias C;Raj A
轴突运输缺陷可能在一定程度上支持阿尔茨海默病（AD）和其他非淀粉样变性牛头病之间观察到的病理生理差异。特别是，病理性tau变异可能具有分子特性，使运动蛋白失调，运动蛋白以疾病特异性的方式负责tau的顺行定向运输。在这里，我们开发了tau修饰轴突运输的第一个计算模型，该模型在tau病理学的传播中产生定向偏差。我们使用生物学上合理的参数和时间尺度模拟了多室双神经元系统中可溶性和不可溶性tau物种的时空分布。tau输运反馈参数平衡的变化会导致系统中可溶性和不可溶性tau分布的逆行和逆行偏差。聚集和破碎参数也可以扰乱这种平衡，表明这些不同的分子过程之间存在复杂的相互作用。重要的是，我们表明该模型忠实地再现了类广告和非类广告小鼠脑损伤模型中的特征网络传播偏差。因此，Tau转运反馈可能有助于将Tau构象状态的微观差异与由此产生的临床表现的多样性联系起来。轴突蛋白tau的错误折叠和扩散是许多神经退行性疾病的病理学特征，包括阿尔茨海默病和额颞叶痴呆。tau蛋白错误折叠如何导致具有不同神经病理学和临床表现的疾病是正在进行的研究的主题。尽管目前的证据表明，tau蛋白所采用的特定构象影响着它在整个大脑中传播的位置，但一个机械的解释仍然难以捉摸。在这里，我们提出轴突运输的conformer特异性失调可能导致定向偏倚传播，我们采用数学模型来探索tau如何在这种运输反馈机制的背景下在神经元之间传播。我们发现构象特定的反馈足够灵活，可以解释任何方向的偏差，并彻底探索这种偏差是如何作为模型关键参数的函数出现的。此外，该模型再现了在两类体内tau病变模型中观察到的方向性的时间进化，表明运输反馈足以解释tau作为构象函数的差异传播。
Defects in axonal transport may partly underpin the differences between the observed pathophysiology of Alzheimer’s disease (AD) and that of other non-amyloidogenic tauopathies. Particularly, pathological tau variants may have molecular properties that dysregulate motor proteins responsible for the anterograde-directed transport of tau in a disease-specific fashion. Here we develop the first computational model of tau-modified axonal transport that produces directional biases in the spread of tau pathology. We simulated the spatiotemporal profiles of soluble and insoluble tau species in a multicompartment, two-neuron system using biologically plausible parameters and time scales. Changes in the balance of tau transport feedback parameters can elicit anterograde and retrograde biases in the distributions of soluble and insoluble tau between compartments in the system. Aggregation and fragmentation parameters can also perturb this balance, suggesting a complex interplay between these distinct molecular processes. Critically, we show that the model faithfully recreates the characteristic network spread biases in both AD-like and non-AD-like mouse tauopathy models. Tau transport feedback may therefore help link microscopic differences in tau conformational states and the resulting variety in clinical presentations. The misfolding and spread of the axonal protein tau is a hallmark of the pathology of many neurodegenerative disorders, including Alzheimer’s disease and frontotemporal lobar dementia. How tau misfolding causes disorders with distinct neuropathology and clinical presentations is the subject of ongoing research. Although current evidence suggests that the specific conformations tau adopts affect where it spreads throughout the brain, a mechanistic explanation has remained elusive. Here we propose that the conformer-specific dysregulation of axonal transport can lead to directionally biased spread, and we employ a mathematical model to explore how tau spreads between neurons in the context of this transport feedback mechanism. We find that conformation-specific feedback is flexible enough to explain bias in either direction and thoroughly explore how this bias emerges as a function of the model’s key parameters. Further, the model reproduces the temporal evolution of directionality observed in two classes of in vivo tauopathy models, demonstrating that transport feedback is sufficient to explain differential tau spread as a function of conformation.
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Tau通过调节动力蛋白和动力蛋白团队施加的力来指导细胞内贩运。
DOI：
10.1111/tra.12537
发表时间：
2018-03
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Chaudhary AR;Berger F;Berger CL;Hendricks AG
通讯作者：
Hendricks AG
影响因子：
34.7
作者：
Frost, Bess;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
影响因子：
4.8
作者：
Katsikoudi, Antigoni;Ficulle, Elena;Bose, Suchira
通讯作者：
Bose, Suchira
DOI：
10.1098/rspa.2018.0511
发表时间：
2018-12-01
影响因子：
3.5
作者：
Kuznetsov, I. A.;Kuznetsov, A. V.
通讯作者：
Kuznetsov, A. V.
DOI：
10.1088/0953-8984/25/46/463101
发表时间：
2013-11-20
期刊：
Journal of physics. Condensed matter : an Institute of Physics journal
影响因子：
--
作者：
Kolomeisky AB
通讯作者：
Kolomeisky AB