Measurement of Tau Filament Fragmentation Provides Insights into Prion-like Spreading.
Measurement of Tau Filament Fragmentation Provides Insights into Prion-like Spreading.
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DOI：
10.1021/acschemneuro.8b00094
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发表时间：
2018-06-20
影响因子：
5
通讯作者：
Klenerman D
中科院分区：
文献类型：
--
作者：
Kundel F;Hong L;Falcon B;McEwan WA;Michaels TCT;Meisl G;Esteras N;Abramov AY;Knowles TJP;Goedert M;Klenerman D
淀粉样蛋白的有序组装导致广泛的常见神经退行性疾病，包括阿尔茨海默病和帕金森病。这些疾病与朊病毒疾病有共同的特征，其中错误折叠的蛋白质可以自我复制并在不同宿主之间传播疾病。破译聚集体放大的分子机制对于理解病理性沉积物如何在大脑中传播并驱动疾病是至关重要的。在这里，我们使用单分子显微镜来研究tau在单个聚集体水平上的组装和复制。我们发现，tau聚集体具有通过丝断裂扩增的内在能力，并通过动力学建模确定了该复制过程的倍增时间。然后，我们模拟了聚集体通过大脑的传播时间，并发现这与阿尔茨海默病和tau蛋白病实验模型中病理性tau沉积物传播的观察时间框架非常一致。通过这项工作，我们开始了解控制tau蛋白和其他淀粉样蛋白在人脑中扩散速率的物理参数。
The ordered assembly of amyloidogenic proteins causes a wide spectrum of common neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. These diseases share common features with prion diseases, in which misfolded proteins can self-replicate and transmit disease across different hosts. Deciphering the molecular mechanisms that underlie the amplification of aggregates is fundamental for understanding how pathological deposits can spread through the brain and drive disease. Here, we used single-molecule microscopy to study the assembly and replication of tau at the single aggregate level. We found that tau aggregates have an intrinsic ability to amplify by filament fragmentation, and determined the doubling times for this replication process by kinetic modeling. We then simulated the spreading time for aggregates through the brain and found this to be in good agreement with both the observed time frame for spreading of pathological tau deposits in Alzheimer’s disease and in experimental models of tauopathies. With this work we begin to understand the physical parameters that govern the spreading rates of tau and other amyloids through the human brain.
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影响因子：
12.7
作者：
Braak, Heiko;Del Tredici, Kelly
通讯作者：
Del Tredici, Kelly
DOI：
10.1074/jbc.m114.589309
发表时间：
2015-01-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Falcon B;Cavallini A;Angers R;Glover S;Murray TK;Barnham L;Jackson S;O'Neill MJ;Isaacs AM;Hutton ML;Szekeres PG;Goedert M;Bose S
通讯作者：
Bose S
影响因子：
3.2
作者：
Klingstedt T;Aslund A;Simon RA;Johansson LB;Mason JJ;Nyström S;Hammarström P;Nilsson KP
通讯作者：
Nilsson KP
影响因子：
4.3
作者：
Brelstaff, Jack;Ossola, Bernardino;Tolkovsky, Aviva M.
通讯作者：
Tolkovsky, Aviva M.
影响因子：
2.5
作者：
Azevedo, Frederico A. C.;Carvalho, Ludmila R. B.;Herculano-Houzel, Suzana
通讯作者：
Herculano-Houzel, Suzana