The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity.
The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity.
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DOI：
10.1002/jnr.21850
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发表时间：
2009-02
影响因子：
4.2
通讯作者：
Brady, Scott T.
中科院分区：
文献类型：
--
作者：
LaPointe, Nichole E.;Morfini, Gerardo;Pigino, Gustavo;Gaisina, Irina N.;Kozikowski, Alan P.;Binder, Lester I.;Brady, Scott T.
阿尔茨海默病（AD）和其他tau蛋白病的神经病理学特征是微管相关蛋白tau的丝状沉积，但tau聚合和神经毒性之间的关系尚不清楚。在这里，我们研究了丝状tau蛋白对快速轴突运输（FAT）的影响，使用分离的鱿鱼轴浆。单体和丝状形式的重组人tau蛋白灌注在轴浆中，其对驱动蛋白和动力蛋白依赖的FAT率的影响通过视频显微镜进行评估。虽然在生理浓度下灌注单体tau蛋白没有显示出任何效果，但相同浓度的tau蛋白丝选择性地抑制了前级（驱动蛋白依赖性）FAT，触发了轴浆囊泡中常规驱动蛋白的释放。药理学实验表明，tau蛋白丝对FAT的影响是通过蛋白磷酸酶1（PP 1）和糖原合成酶激酶-3（GSK-3）的活性介导的。此外，缺失分析表明，这些影响取决于保守的18个氨基酸序列的氨基末端的tau蛋白。有趣的是，缺乏分子C末端一半（包括微管结合区）的单体tau亚型概括了全长丝状tau的作用。我们的研究结果表明，病理性tau蛋白聚集通过改变FAT的调节途径而导致神经退行性变。
The neuropathology of Alzheimer's disease (AD) and other tauopathies is characterized by filamentous deposits of the microtubule-associated protein tau, but the relationship between tau polymerization and neurotoxicity is unknown. Here, we examined effects of filamentous tau on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric and filamentous forms of recombinant human tau were perfused in axoplasm, and their effects on kinesin- and dynein-dependent FAT rates were evaluated by video microscopy. Although perfusion of monomeric tau at physiological concentrations showed no effect, tau filaments at the same concentrations selectively inhibited antero-grade (kinesin-dependent) FAT, triggering the release of conventional kinesin from axoplasmic vesicles. Pharmacological experiments indicated that the effect of tau filaments on FAT is mediated by protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK-3) activities. Moreover, deletion analysis suggested that these effects depend on a conserved 18-amino-acid sequence at the amino terminus of tau. Interestingly, monomeric tau isoforms lacking the C-terminal half of the molecule (including the microtubule binding region) recapitulated the effects of full-length filamentous tau. Our results suggest that pathological tau aggregation contributes to neurodegeneration by altering a regulatory pathway for FAT.
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DOI：
10.1083/jcb.138.5.1067
发表时间：
1997-09-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Felgner H;Frank R;Biernat J;Mandelkow EM;Mandelkow E;Ludin B;Matus A;Schliwa M
通讯作者：
Schliwa M
影响因子：
2.1
作者：
Ferrer, I.;Gomez-Isla, T.;Avila, J.
通讯作者：
Avila, J.
影响因子：
2.9
作者：
Gamblin, TC;Berry, RW;Binder, LI
通讯作者：
Binder, LI
DOI：
10.1083/jcb.120.2.467
发表时间：
1993-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bloom GS;Richards BW;Leopold PL;Ritchey DM;Brady ST
通讯作者：
Brady ST
影响因子：
2.9
作者：
Berry, RW;Abraha, A;Binder, LI
通讯作者：
Binder, LI