Elton Laboratory for Molecular Neuroendocrinology, Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv, Israel.
PLoS One. 2019 Mar 13;14(3):e0213666. doi: 10.1371/journal.pone.0213666. eCollection 2019.
The microtubule (MT) associated protein Tau is instrumental for the regulation of MT assembly and dynamic instability, orchestrating MT-dependent cellular processes. Aberration in Tau post-translational modifications ratio deviation of spliced Tau isoforms 3 or 4 MT binding repeats (3R/4R) have been implicated in neurodegenerative tauopathies. Activity-dependent neuroprotective protein (ADNP) is vital for brain formation and cognitive function. ADNP deficiency in mice causes pathological Tau hyperphosphorylation and aggregation, correlated with impaired cognitive functions. It has been previously shown that the ADNP-derived peptide NAP protects against ADNP deficiency, exhibiting neuroprotection, MT interaction and memory protection. NAP prevents MT degradation by recruitment of Tau and end-binding proteins to MTs and expression of these proteins is required for NAP activity. Clinically, NAP (davunetide, CP201) exhibited efficacy in prodromal Alzheimer's disease patients (Tau3R/4R tauopathy) but not in progressive supranuclear palsy (increased Tau4R tauopathy). Here, we examined the potential preferential interaction of NAP with 3R vs. 4R Tau, toward personalized treatment of tauopathies. Affinity-chromatography showed that NAP preferentially interacted with Tau3R protein from rat brain extracts and fluorescence recovery after photobleaching assay indicated that NAP induced increased recruitment of human Tau3R to MTs under zinc intoxication, in comparison to Tau4R. Furthermore, we showed that NAP interaction with tubulin (MTs) was inhibited by obstruction of Tau-binding sites on MTs, confirming the requirement of Tau-MT interaction for NAP activity. The preferential interaction of NAP with Tau3R may explain clinical efficacy in mixed vs. Tau4R pathologies, and suggest effectiveness in Tau3R neurodevelopmental disorders.
微管（MT）相关蛋白 Tau 对于 MT 组装和动态不稳定性的调节至关重要，协调 MT 依赖的细胞过程。 Tau 翻译后修饰比偏差的异常，即剪接 Tau 异构体 3 或 4 MT 结合重复（3R/4R），与神经退行性 Tau 病有关。活性依赖性神经保护蛋白（ADNP）对于大脑形成和认知功能至关重要。ADNP 缺乏症在小鼠中导致病理性 Tau 过度磷酸化和聚集，与认知功能受损相关。先前已经表明，ADNP 衍生肽 NAP 可防止 ADNP 缺乏，表现出神经保护、MT 相互作用和记忆保护。NAP 通过招募 Tau 和末端结合蛋白到 MT 上来防止 MT 降解，并且这些蛋白的表达对于 NAP 活性是必需的。临床上，NAP（davunetide，CP201）在前驱期阿尔茨海默病患者（Tau3R/4R Tau 病）中表现出疗效，但在进行性核上性麻痹（增加 Tau4R Tau 病）中无效。在这里，我们研究了 NAP 与 3R 与 4R Tau 优先相互作用的潜力，以针对 Tau 病进行个体化治疗。亲和层析表明，NAP 优先与来自大鼠脑提取物的 Tau3R 蛋白相互作用，荧光恢复后光漂白测定表明，与 Tau4R 相比，NAP 在锌中毒下诱导更多的人 Tau3R 招募到 MT 上。此外，我们表明，NAP 与微管蛋白（MTs）的相互作用被 MT 上 Tau 结合位点的阻塞所抑制，证实了 Tau-MT 相互作用对于 NAP 活性的需求。NAP 与 Tau3R 的优先相互作用可能解释了在混合 vs. Tau4R 病理学中的临床疗效，并表明在 Tau3R 神经发育障碍中的有效性。
