RNA Binds to Tau Fibrils and Sustains Template-Assisted Growth.
RNA Binds to Tau Fibrils and Sustains Template-Assisted Growth.
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DOI：
10.1021/acs.biochem.5b00453
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发表时间：
2015-08-04
期刊：
影响因子：
2.9
通讯作者：
Margittai M
中科院分区：
文献类型：
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作者：
Dinkel PD;Holden MR;Matin N;Margittai M
Tau原纤维是阿尔茨海默病中神经系统病变的主要蛋白质成分。虽然RNA分子被隔离到这些病变中，但它们与Tau原纤维的关系知之甚少。然而，这种理解是重要的，因为短纤维可以在神经元之间转移，而包括RNA在内的非蛋白质因子可以在调节后一过程中发挥决定性作用。在这里，我们使用沉降分析结合电子顺磁共振（EPR），荧光和吸收光谱，以确定RNA对Tau原纤维结构和生长的影响。我们观察到，在RNA存在下，三重复（3R）和四重复（4R）Tau形成具有平行、对齐排列的β链的原纤维，并表现出不对称的接种屏障，其中4R Tau生长在3R Tau种子上，但反之亦然。这些结构特征与先前观察到的肝素诱导的原纤维相似，表明基本构象性质是保守的，尽管它们是成核剂的分子差异。此外，RNA维持模板辅助的生长并结合到原纤维表面，并且可以被肝素交换。这些发现表明，除了介导纤维化之外，装饰Tau原纤维表面的辅因子可以调节生物相互作用，从而影响Tau病理在人脑中的传播。
Tau fibrils are the main proteinacious components of neurofibrillary lesions in Alzheimer disease. Although RNA molecules are sequestered into these lesions, their relationship to Tau fibrils is only poorly understood. Such understanding, however, is important, as short fibrils can transfer between neurons and nonproteinacious factors including RNA could play a defining role in modulating the latter process. Here, we used sedimentation assays combined with electron paramagnetic resonance (EPR), fluorescence, and absorbance spectroscopy to determine the effects of RNA on Tau fibril structure and growth. We observe that, in the presence of RNA, three-repeat (3R) and four-repeat (4R) Tau form fibrils with parallel, in-register arrangement of β-strands and exhibit an asymmetric seeding barrier in which 4R Tau grows onto 3R Tau seeds but not vice versa. These structural features are similar to those previously observed for heparin-induced fibrils, indicating that basic conformational properties are conserved, despite their being molecular differences of the nucleating agents. Furthermore, RNA sustains template-assisted growth and binds to the fibril surface and can be exchanged by heparin. These findings suggest that, in addition to mediating fibrillization, cofactors decorating the surface of Tau fibrils may modulate biological interactions and thereby influence the spreading of Tau pathology in the human brain.