Hyperphosphorylation-induced tau oligomers.
Hyperphosphorylation-induced tau oligomers.
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DOI：
10.3389/fneur.2013.00112
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发表时间：
2013
影响因子：
3.4
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Iqbal K;Gong CX;Liu F
在正常成人大脑中，微管相关蛋白（MAP） tau每摩尔含有2-3个磷酸盐，在这种磷酸化水平下，它是一种可溶性细胞质蛋白。正常的脑tau蛋白与微管蛋白相互作用，促进其组装成微管，并稳定这些原纤维。在阿尔茨海默病（AD）中，脑tau是三到四倍的过度磷酸化。异常过度磷酸化的tau蛋白与正常tau蛋白结合而不是与微管蛋白结合，这种结合导致tau寡聚物的形成。tau低聚物可以在200,000 × g下沉积，而正常的tau在这些条件下仍留在上清中。异常过度磷酸化的tau蛋白不仅能够隔离正常的tau蛋白，还能够隔离MAP MAP1和MAP2，并导致由这些蛋白促进的微管网络的破坏。与Aβ和朊蛋白（PrP）寡聚物不同，AD和相关tau病中的tau寡聚是过度磷酸化依赖的；在体外用蛋白磷酸酶2A （PP2A）去磷酸化AD - P-tau抑制PP2A-AD - P-tau的再过磷酸化，并使用多种tau蛋白激酶的组合促进其寡聚化。在生理组装条件下，AD - P-tau很容易自组装成成对的螺旋细丝。额颞叶痴呆中发现的错义tau突变明显通过促进其异常过度磷酸化而导致tau寡聚化和神经原纤维病理。如在唐氏综合症、皮克病和进行性核上性麻痹中，改变3-repeat: 4-repeat tau 1:1比例的tau的选择性剪接失调导致tau的异常过度磷酸化。
In normal adult brain the microtubule associated protein (MAP) tau contains 2–3 phosphates per mol of the protein and at this level of phosphorylation it is a soluble cytosolic protein. The normal brain tau interacts with tubulin and promotes its assembly into microtubules and stabilizes these fibrils. In Alzheimer disease (AD) brain tau is three to fourfold hyperphosphorylated. The abnormally hyperphosphorylated tau binds to normal tau instead of the tubulin and this binding leads to the formation of tau oligomers. The tau oligomers can be sedimented at 200,000 × g whereas the normal tau under these conditions remains in the supernatant. The abnormally hyperphosphorylated tau is capable of sequestering not only normal tau but also MAP MAP1 and MAP2 and causing disruption of the microtubule network promoted by these proteins. Unlike Aβ and prion protein (PrP) oligomers, tau oligomerization in AD and related tauopathies is hyperphosphorylation-dependent; in vitro dephosphorylation of AD P-tau with protein phosphatase 2A (PP2A) inhibits and rehyperphosphorylation of the PP2A-AD P-tau with more than one combination of tau protein kinases promotes its oligomerization. In physiological assembly conditions the AD P-tau readily self-assembles into paired helical filaments. Missense tau mutations found in frontotemporal dementia apparently lead to tau oligomerization and neurofibrillary pathology by promoting its abnormal hyperphosphorylation. Dysregulation of the alternative splicing of tau that alters the 1:1 ratio of the 3-repeat: 4-repeat taus such as in Down syndrome, Pick disease, and progressive supranuclear palsy leads to the abnormal hyperphosphorylation of tau.
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DOI：
10.1083/jcb.115.3.717
发表时间：
1991-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Butner KA;Kirschner MW
通讯作者：
Kirschner MW
影响因子：
4.8
作者：
Ackmann, M;Wiech, H;Mandelkow, E
通讯作者：
Mandelkow, E
影响因子：
82.9
作者：
Alonso, AD;GrundkeIqbal, I;Iqbal, K
通讯作者：
Iqbal, K
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA