Local structural preferences in shaping tau amyloid polymorphism.
Local structural preferences in shaping tau amyloid polymorphism.
复制标题
DOI：
10.1038/s41467-024-45429-2
复制
发表时间：
2024-02-03
影响因子：
16.6
通讯作者：
Schymkowitz, Joost
中科院分区：
文献类型：
--
作者：
Louros, Nikolaos;Wilkinson, Martin;Tsaka, Grigoria;Ramakers, Meine;Morelli, Chiara;Garcia, Teresa;Gallardo, Rodrigo;D'Haeyer, Sam;Goossens, Vera;Audenaert, Dominique;Thal, Dietmar Rudolf;Mackenzie, Ian R.;Rademakers, Rosa;Ranson, Neil A.;Radford, Sheena E.;Rousseau, Frederic;Schymkowitz, Joost
tau病包括一组以多样的tau淀粉样蛋白纤维结构为特征的神经退行性疾病。在牛头病变中多态性的持久性表明，不同的病理条件决定了每种疾病所采用的多态性。然而，tau淀粉样蛋白核心的内在结构倾向对纤维多态性的影响程度仍不确定。结合实验方法，我们在这里确定了一个新的淀粉样蛋白基序PAM4（多态淀粉样蛋白基序重复4），作为tau多态性的重要因素。计算每残基对不同病理性tau结构的原纤维核心稳定性的贡献表明，PAM4在保持淀粉样蛋白多态性的结构完整性方面起着核心作用。与此一致的是，对合成PAM4肽形成的原纤维的低温电镜结构分析表明，该序列采用了与不同疾病相关的tau菌株密切对应的替代结构。此外，细胞内实验显示，PAM4缺失阻碍了从阿尔茨海默病、皮质基底变性和进行性核上性麻痹患者中提取的tau聚集体的细胞植入效率，强调了PAM4在这些tau病变中的关键作用。总之，我们的研究结果强调了淀粉样蛋白核心片段内在结构倾向的重要性，它决定了细胞中tau蛋白的结构，并在疾病中传播淀粉样蛋白结构。在这项工作中，作者使用冷冻电镜、细胞内实验和生物物理分析相结合的方法，解码了tau的聚集倾向，揭示了其初级序列中的5个中心热点，并确定PAM4是决定从阿尔茨海默病、皮质基底变性和进进性核上性麻痹患者中提取的tau聚集物的结构和细胞增殖的短片段。
Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, the extent to which intrinsic structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Using a combination of experimental approaches, we here identify a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Calculation of per-residue contributions to the stability of the fibril cores of different pathologic tau structures suggests that PAM4 plays a central role in preserving structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide shows that the sequence adopts alternative structures that closely correspond to distinct disease-associated tau strains. Furthermore, in-cell experiments revealed that PAM4 deletion hampers the cellular seeding efficiency of tau aggregates extracted from Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4’s pivotal role in these tauopathies. Together, our results highlight the importance of the intrinsic structural propensity of amyloid core segments to determine the structure of tau in cells, and in propagating amyloid structures in disease. In this work, using a combination of Cryo-EM, in-cell experiments and biophysical analysis, the authors decoded the aggregation propensity of tau, revealing 5 central hot spots in its primary sequence and identify PAM4 as short segment that determines both the structure, as well as the cellular propagation of tau aggregates extracted from Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy patients.
登录
查看更多内容
影响因子：
16.6
作者：
Louros N;Ramakers M;Michiels E;Konstantoulea K;Morelli C;Garcia T;Moonen N;D'Haeyer S;Goossens V;Thal DR;Audenaert D;Rousseau F;Schymkowitz J
通讯作者：
Schymkowitz J
影响因子：
2.9
作者：
Jeganathan, Sadasivam;von Bergen, Martin;Mandelkow, Eckhard
通讯作者：
Mandelkow, Eckhard
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
3
作者：
Kremer, JR;Mastronarde, DN;McIntosh, JR
通讯作者：
McIntosh, JR