Fracture and Growth Are Competing Forces Determining the Fate of Conformers in Tau Fibril Populations.
Fracture and Growth Are Competing Forces Determining the Fate of Conformers in Tau Fibril Populations.
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断裂和生长是确定tau原纤维种群中构象异构体的命运的竞争力。
DOI：
10.1074/jbc.m116.715557
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发表时间：
2016-06-03
期刊：
影响因子：
--
通讯作者：
Margittai M
中科院分区：
文献类型：
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作者：
Meyer V;Holden MR;Weismiller HA;Eaton GR;Eaton SS;Margittai M
Tau原纤维是病理聚集体，可以在神经元之间转移，然后通过模板辅助转化招募可溶性Tau单体。不同纤维多态性的繁殖被认为是阿尔茨海默病和其他tau病表型多样性的一个促进因素。我们发现由截断版K18（残基244-372）组成的均匀的Tau原纤维群体在经过多次播种和生长循环后逐渐转化为一组新的原纤维构象。利用双电子-电子共振（DEER）光谱，我们观察到纤维芯311和328位自旋标签之间的距离逐渐减小。浊度、形态和蛋白酶敏感性的变化证实了这一发现。最初在搅拌条件下形成的原纤维与经过多次播种循环后静止形成的原纤维相比，表现出更高的脆弱性。静止形成的原纤维以加速生长为特征。不同构象之间脆性和生长的差异解释了孵育条件的变化如何导致小原纤维亚群的扩增。在静止条件下，纤维断裂最小，生长更快的原纤维具有选择优势。这些发现具有普遍的重要性，因为它们表明，在人脑中原纤维繁殖过程中，选择压力的变化可能导致新的原纤维构象的出现，并带来不同的临床病理后果。
Tau fibrils are pathological aggregates that can transfer between neurons and then recruit soluble Tau monomers by template-assisted conversion. The propagation of different fibril polymorphs is thought to be a contributing factor to phenotypic diversity in Alzheimer disease and other Tauopathies. We found that a homogeneous population of Tau fibrils composed of the truncated version K18 (residues 244–372) gradually converted to a new set of fibril conformers when subjected to multiple cycles of seeding and growth. Using double electron-electron resonance (DEER) spectroscopy, we observed that the distances between spin labels at positions 311 and 328 in the fibril core progressively decreased. The findings were corroborated by changes in turbidity, morphology, and protease sensitivity. Fibrils that were initially formed under stirring conditions exhibited an increased fragility compared with fibrils formed quiescently after multiple cycles of seeding. The quiescently formed fibrils were marked by accelerated growth. The difference in fragility and growth between the different conformers explains how the change in incubation condition could lead to the amplification of a minor subpopulation of fibrils. Under quiescent conditions where fibril breakage is minimal, faster growing fibrils have a selective advantage. The findings are of general importance as they suggest that changes in selective pressures during fibril propagation in the human brain could result in the emergence of new fibril conformers with varied clinicopathological consequences.