Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration
Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration
复制标题
DOI：
10.1038/emboj.2011.376
复制
发表时间：
2011-11-30
期刊：
影响因子：
11.4
通讯作者：
Mandelkow, Eckhard
中科院分区：
文献类型：
--
作者：
Li, Xiaoyu;Kumar, Yatender;Mandelkow, Eckhard
Tau从轴突到神经元的体树突区室的错误分选是阿尔茨海默病的标志，但对正常分选和病理失败的机制知之甚少。在这里，我们使用了几种标记有光转换Dendra 2的Tau构建体来分析其在极化神经元中的移动性。这揭示了一种新的分选机制-轴突起始段（AIS）中的逆行屏障起细胞整流器的作用。它允许轴突Tau的顺行流动，但阻止逆行流回到索马和树突。该屏障需要Tau与微管结合，但不需要F-肌动蛋白，因此与AIS处的膜相关蛋白的分选不同。当Tau在其重复结构域中被磷酸化并从微管分离时，例如，通过激酶MARK/Par 1，屏障被破坏。这些观察结果将神经退行性疾病中Tau错误分选和过度磷酸化的病理学标志联系起来。The EMBO Journal（2011）30，4825-4837. doi：10.1038/doj.2011.376; 2011年10月18日在线发布
Missorting of Tau from axons to the somatodendritic compartment of neurons is a hallmark of Alzheimer's disease, but the mechanisms underlying normal sorting and pathological failure are poorly understood. Here, we used several Tau constructs labelled with photoconvertible Dendra2 to analyse its mobility in polarized neurons. This revealed a novel mechanism of sorting-a retrograde barrier in the axon initial segment (AIS) operating as cellular rectifier. It allows anterograde flow of axonal Tau but prevents retrograde flow back into soma and dendrites. The barrier requires binding of Tau to microtubules but does not require F-actin and thus is distinct from the sorting of membrane-associated proteins at the AIS. The barrier breaks down when Tau is phosphorylated in its repeat domain and detached from microtubules, for example, by the kinase MARK/Par1. These observations link the pathological hallmarks of Tau missorting and hyperphosphorylation in neurodegenerative diseases. The EMBO Journal (2011) 30, 4825-4837. doi:10.1038/emboj.2011.376; Published online 18 October 2011