Tau phosphorylation and PAD exposure in regulation of axonal growth.
Tau phosphorylation and PAD exposure in regulation of axonal growth.
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Tau磷酸化和垫垫暴露于轴突生长的调节中。
DOI：
10.3389/fcell.2022.1023418
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
Tau是一种微管相关的磷蛋白，主要存在于神经元中。流行的教条继续将微管稳定定义为tau在体内的主要功能，尽管有几条证据表明情况并非如此。最重要的是，tau基因敲除小鼠在轴突生长和神经元迁移方面存在缺陷，同时仍具有广泛的微管网络。相反，越来越多的证据表明，tau蛋白可能具有通过激活神经元信号通路调节快速轴突运输（FAT）的主要功能。先前的研究在tau蛋白N-末端鉴定了磷酸酶激活结构域（PAD），其通常被隔离，但在tau蛋白病中组成性暴露。当暴露时，PAD激活涉及PP 1和GSK 3 β的信号级联，其影响细胞功能，包括从驱动蛋白释放货物。此外，我们发现PAD暴露可以通过T205处的单一磷酸化来调节。PAD的暴露是多种tau蛋白病的早期事件，也是与tau蛋白过度磷酸化相关的神经变性的主要促成因素。然而，tau PAD暴露对顺行性FAT的影响提出了一种有趣的可能性，即该途径可能是通过tau的位点特异性磷酸化和PP1和GSK 3 β的瞬时激活来生理调节货物递送的机制。值得注意的是，已经有证据表明在需要货物运输的部位对PP1和GSK 3 β进行了局部控制。 研究方法：为了研究这一假设，我们首先评估了发育过程中原代海马神经元中tau PAD暴露、pT205 tau磷酸化和活性GSK 3 β的细胞定位。其次，我们分析了在用全长hTau40-WT、hTau40-Δ PAD或hTau40-T205A转染后tau敲除神经元的轴突生长。 结果和讨论：本文提供的结果表明，通过局部调节的PAD暴露瞬时激活PP1-GSK3 β信号通路是货物递送的机制，因此对发育中神经元的神经突生长很重要。
Introduction: Tau is a microtubule associated phosphoprotein found principally in neurons. Prevailing dogma continues to define microtubule stabilization as the major function of tau in vivo, despite several lines of evidence suggesting this is not the case. Most importantly, tau null mice have deficits in axonal outgrowth and neuronal migration while still possessing an extensive microtubule network. Instead, mounting evidence suggests that tau may have a major function in the regulation of fast axonal transport (FAT) through activation of neuronal signaling pathways. Previous studies identified a phosphatase activating domain (PAD) at the tau N-terminal that is normally sequestered, but is constitutively exposed in tauopathies. When exposed, the PAD activates a signaling cascade involving PP1 and GSK3β which affects cellular functions including release of cargo from kinesin. Furthermore, we discovered that PAD exposure can be regulated by a single phosphorylation at T205. Exposure of the PAD is an early event in multiple tauopathies and a major contributing factor to neurodegeneration associated with tau hyperphosphorylation. However, effects of tau PAD exposure on anterograde FAT raised the interesting possibility that this pathway may be a mechanism for physiological regulation of cargo delivery through site-specific phosphorylation of tau and transient activation of PP1 and GSK3β. Significantly, there is already evidence of local control of PP1 and GSK3β at sites which require cargo delivery. Methods: To investigate this hypothesis, first we evaluated cellular localization of tau PAD exposure, pT205 tau phosphorylation, and active GSK3β in primary hippocampal neurons during development. Second, we analyzed the axonal outgrowth of tau knockout neurons following transfection with full length hTau40-WT, hTau40-ΔPAD, or hTau40-T205A. Results and Discussion: The results presented here suggest that transient activation of a PP1-GSK3β signaling pathway through locally regulated PAD exposure is a mechanism for cargo delivery, and thereby important for neurite outgrowth of developing neurons.
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