Pathogenic missense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps.
Pathogenic missense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps.
复制标题
DOI：
10.1111/j.1471-4159.2008.05692.x
复制
发表时间：
2008-11
影响因子：
4.7
通讯作者：
Kuret, Jeff
中科院分区：
文献类型：
--
作者：
Chang, Edward;Kim, Sohee;Yin, Haishan;Nagaraja, Haikady N.;Kuret, Jeff
编码tau蛋白的MAPT基因的突变导致与额颞叶变性相关的神经系统病变形成、神经变性和认知能力下降。虽然一些致病性突变影响MAPT内含子，导致异常剪接模式，但大多数发生在tau编码序列中，导致tau一级结构中的单个氨基酸变化。根据它们在多肽链内的位置，已经报道tau错义突变增加聚集倾向。为了确定聚集行为中突变相关变化的潜在机制，使用电子显微镜测定方法在体外检查了在全长四重复人类tau背景中制备的重组致病突变体R5L、G272V、P301L、V337M和R406W的灭活作为时间和亚微摩尔tau浓度的函数。然后通过直接测量和数学模拟来估计聚集成核和延伸阶段的动力学常数。结果表明，突变体在聚集倾向上彼此不同，并且与野生型tau不同。G272V和P301L突变增加了丝状体成核和延伸反应的速率，而R5L和V337M仅增加了成核阶段。R406W在任何动力学参数上与野生型没有差异。结果表明，错义突变可以在聚集途径的不同阶段直接促进tau蛋白丝的形成。
Mutations in the MAPT gene encoding tau protein lead to neurofibrillary lesion formation, neurodegeneration, and cognitive decline associated with frontotemporal lobar degeneration. While some pathogenic mutations affect MAPT introns, resulting in abnormal splicing patterns, the majority occur in the tau coding sequence leading to single amino acid changes in tau primary structure. Depending on their location within the polypeptide chain, tau missense mutations have been reported to augment aggregation propensity. To determine the mechanisms underlying mutation-associated changes in aggregation behavior, the fibrillization of recombinant pathogenic mutants R5L, G272V, P301L, V337M, and R406W prepared in a full-length four-repeat human tau background was examined in vitro as a function of time and submicromolar tau concentrations using electron microscopy assay methods. Kinetic constants for nucleation and extension phases of aggregation were then estimated by direct measurement and mathematical simulation. Results indicated that the mutants differ from each other and from wild-type tau in their aggregation propensity. G272V and P301L mutations increased the rates of both filament nucleation and extension reactions, whereas R5L and V337M increased only the nucleation phase. R406W did not differ from wild-type in any kinetic parameter. The results show that missense mutations can directly promote tau filament formation at different stages of the aggregation pathway.
登录
查看更多内容
影响因子：
4.8
作者：
Ackmann, M;Wiech, H;Mandelkow, E
通讯作者：
Mandelkow, E
影响因子：
5.3
作者：
Grover, A;England, E;Hutton, M
通讯作者：
Hutton, M
影响因子：
3.5
作者：
Hasegawa, M;Smith, MJ;Goedert, M
通讯作者：
Goedert, M
影响因子：
4.8
作者：
Goode, BL;Chau, M;Feinstein, SC
通讯作者：
Feinstein, SC
影响因子：
2.9
作者：
Gamblin, TC;Berry, RW;Binder, LI
通讯作者：
Binder, LI