Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition.
Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition.
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DOI：
10.1016/j.neurobiolaging.2016.07.015
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发表时间：
2016-11
影响因子：
4.2
通讯作者：
Kanaan NM
中科院分区：
文献类型：
--
作者：
Cox K;Combs B;Abdelmesih B;Morfini G;Brady ST;Kanaan NM
错误折叠的 tau 蛋白是 tau 病的特征，但 tau 内含物的亚型组成因 tau 病而异。利用最长的 tau 异构体（包含四个微管结合重复序列，即 4-repeat tau）的聚集体，我们最近描述了一种直接毒性机制，涉及暴露 tau 中的 N 末端磷酸酶激活结构域 (PAD)，从而触发扰乱轴突运输的信号通路。然而，聚集对其他 tau 亚型的 PAD 暴露的影响尚未被探索。在此，免疫化学测定的结果表明，聚集诱导的 PAD 暴露和寡聚化增加是所有 tau 亚型的共同特征。与由 3 个重复异构体组成的 tau 聚集体相比，由 4 个重复异构体组成的 tau 聚集体的 PAD 暴露和寡聚化程度更大。重要的是，所有亚型的聚集体都表现出足够的 PAD 暴露，从而显着损害鱿鱼轴浆中的轴突运输。我们还表明，PAD 暴露和寡聚化代表了多种 tau蛋白病的常见病理特征。总的来说，这些结果表明了每种 tau 亚型共有的毒性机制，可能导致不同 tau 病的退化。
Misfolded tau proteins are characteristic of tauopathies, but the isoform composition of tau inclusions varies by tauopathy. Using aggregates of the longest tau isoform (containing four microtubule-binding repeats, 4-repeat tau), we recently described a direct mechanism of toxicity that involves exposure of the N-terminal phosphatase-activating domain (PAD) in tau, which triggers a signaling pathway that disrupts axonal transport. However, the impact of aggregation on PAD exposure for other tau isoforms was unexplored. Here, results from immunochemical assays indicate that aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared to those made of 3-repeat isoforms. Importantly, aggregates of all isoforms exhibited enough PAD exposure to significantly impair axonal transport in the squid axoplasm. We also show that PAD exposure and oligomerization represent common pathological characteristics in multiple tauopathies. Collectively, these results suggest a mechanism of toxicity common to each tau isoform that likely contributes to degeneration in different tauopathies.
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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：
6.1
作者：
Combs B;Hamel C;Kanaan NM
通讯作者：
Kanaan NM
影响因子：
5.3
作者：
Castillo-Carranza, Diana L.;Sengupta, Urmi;Kayed, Rakez
通讯作者：
Kayed, Rakez
影响因子：
82.9
作者：
Alonso, AD;GrundkeIqbal, I;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