AIMS Plectin, a universally expressed multi-functional cytolinker protein, is crucial for intermediate filament networking, including crosstalk withactomyosin and microtubules. In addition to its involvement in a number of diseases affecting skin, skeletal muscle, heart, and other stress-exposed tissues, indications for a neuropathological role of plectin have emerged. Having identified P1c as the major isoform expressed in neural tissues in previous studies, our aim for the present work was to investigate whether, and by which mechanism(s), the targeted deletion of this isoform affects neuritogenesis and proper nerve cell functioning. METHODS For ex vivo phenotyping, we used dorsal root ganglion (DRG) and hippocampal neurons derived from isoform P1c-deficient and plectin-null mice, complemented by in vitro experiments using purified proteins and cell fractions. To assess the physiological significance of the phenotypic alterations observed in P1c-/- deficient neurons, P1c-/- and WT littermate mice were subjected to standard behavioural tests. RESULTS We demonstrate that P1c affects axonal microtubule dynamics by isoform-specific interaction with tubulin. P1c deficiency in neurons leads to altered dynamics of microtubules and excessive association with tau protein, affecting neuritogenesis, neurite branching, growth cone morphology, and translocation and directionality of movement of vesicles and mitochondria. On the organismal level, we found P1c deficiency manifesting as impaired pain sensitivity, diminished learning capabilities, and reduced long-term memory of mice. CONCLUSIONS Revealing a regulatory role of plectin scaffolds in microtubule-dependent nerve cell functions, our results have potential implications for cytoskeleton-related neuropathies.

中文翻译：

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神经元中的凝集素功能障碍导致微管上的 tau 积累，影响神经发生、细胞器运输、疼痛敏感性和记忆

AIMS Plectin 是一种普遍表达的多功能细胞连接蛋白，对于中间丝网络至关重要，包括与肌动球蛋白和微管的串扰。除了涉及影响皮肤、骨骼肌、心脏和其他暴露于压力的组织的许多疾病之外，还出现了 plectin 的神经病理学作用的迹象。在之前的研究中已将 P1c 确定为神经组织中表达的主要同种型，我们目前工作的目标是研究这种同种型的靶向缺失是否以及通过何种机制影响神经发生和正常的神经细胞功能。方法对于离体表型分析，我们使用来自同种型 P1c 缺陷和 plectin 无效小鼠的背根神经节 (DRG) 和海马神经元，辅以使用纯化蛋白质和细胞组分的体外实验。为了评估在 P1c-/- 缺陷神经元中观察到的表型改变的生理意义，对 P1c-/- 和 WT 同窝小鼠进行标准行为测试。结果我们证明 P1c 通过与微管蛋白的亚型特异性相互作用影响轴突微管动力学。神经元中的 P1c 缺乏导致微管动力学改变和与 tau 蛋白的过度关联，影响神经发生、轴突分支、生长锥形态以及囊泡和线粒体运动的易位和方向性。在机体水平上，我们发现 P1c 缺乏表现为小鼠的疼痛敏感性受损、学习能力下降和长期记忆减少。