ADNP/NAP dramatically increase microtubule end-binding protein-Tau interaction: a novel avenue for protection against tauopathy
ADNP/NAP dramatically increase microtubule end-binding protein-Tau interaction: a novel avenue for protection against tauopathy
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DOI：
10.1038/mp.2016.255
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发表时间：
2017-09-01
影响因子：
11
通讯作者：
Gozes, I.
中科院分区：
文献类型：
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作者：
Ivashko-Pachima, Y.;Sayas, C. Laura;Gozes, I.
活动依赖性神经保护蛋白（ADNP）对大脑形成和认知功能至关重要，它在自闭症中发生突变，并与神经退行性/精神疾病相关。 ADNP 的八个氨基酸肽片段 NAP (NAPVSIPQ) 被确定为最小的活性片段，包含 SxIP 微管 (MT) 末端结合蛋白 (EB) 关联基序，并增强 ADNP-EB3 相互作用。 EB1 或 EB3 的耗尽会消除 NAP 对锌中毒的保护作用。此外，NAP 增强 Tau-MT 相互作用，Tau 调节 EB1 和 EB3 在发育神经元细胞中的定位和功能。在这里，我们询问 NAP (ADNP) 如何增强 Tau-MT 相互作用以及这是否由 EB 介导。我们认为这是第一次，NAP 增强了 N1E-115 神经母细胞瘤神经元模型中的内源 EB1 彗星密度。这一发现得到了荧光 EB1 细胞转染和活细胞成像的证实。 NAP 增加了彗星的数量、长度和速度。在分子水平上，NAP 增强 EB3 同二聚体形成，同时降低 EB1-EB3 异二聚体含量并驱动 EB1 和 EB3-Tau 相互作用（显着增加 20 倍），导致在锌中毒下 EB1/EB3 和 Tau 募集到 MT。我们之前的结果表明，虽然 NAP 可以保护神经元样细胞免受氧化应激，但它不能保护 NIH3T3 成纤维细胞。在这里，NAP 并不能保护 NIH3T3 细胞免受锌中毒，除非这些细胞被 Tau 转染。有趣的是，其他MT相关蛋白（MAP）可能会取代Tau，因此，EB-Tau（MAP）相互作用被确定为内源性ADNP神经保护的新靶点，以及以NAP为原型的未来药物开发靶点。
Activity-dependent neuroprotective protein (ADNP), vital for brain formation and cognitive function, is mutated in autism and linked to neurodegenerative/psychiatric diseases. An eight-amino-acid peptide snippet of ADNP, NAP (NAPVSIPQ), identified as a smallest active fragment, includes the SxIP microtubule (MT) end-binding protein (EB) association motif, and enhances ADNP-EB3 interaction. Depletion of EB1 or EB3 abolishes NAP protection against zinc intoxication. Furthermore, NAP enhances Tau-MT interaction, and Tau regulates the localization and function of EB1 and EB3 in developing neuronal cells. Here, we asked how NAP (ADNP) enhances Tau-MT interactions and whether this is mediated by EBs. We showed, for we believe the first time, that NAP augmented endogenous EB1 comet density in the N1E-115 neuroblastoma neuronal model. This finding was substantiated by cell transfection with fluorescent EB1 and live cell imaging. NAP increased comet amounts, length and speed. At the molecular level, NAP enhanced EB3 homodimer formation, while decreasing EB1-EB3 heterodimer content and driving EB1- and EB3-Tau interactions (dramatic 20-fold increases), leading to recruitment of EB1/EB3 and Tau to MTs under zinc intoxication. Our previous results showed that while NAP protected neuronal-like cells against oxidative stress, it did not protect NIH3T3 fibroblasts. Here, NAP did not protect NIH3T3 cells against zinc intoxication, unless these cells were transfected with Tau. Interestingly, other MT associated proteins (MAPs) may replace Tau, thus, EB-Tau (MAPs) interaction is identified as a novel target for endogenous ADNP neuroprotection, and a future target for drug development, with NAP as a prototype.