Effects of P301L-TAU on post-translational modifications of microtubules in human iPSC-derived cortical neurons and TAU transgenic mice.

IF 5.9 2区 医学 Q2 CELL BIOLOGY Neural Regeneration Research Pub Date : 2025-08-01 Epub Date: 2024-06-26 DOI:10.4103/NRR.NRR-D-23-01742
Mohamed Aghyad Al Kabbani, Christoph Köhler, Hans Zempel
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Abstract

JOURNAL/nrgr/04.03/01300535-202508000-00025/figure1/v/2024-09-30T120553Z/r/image-tiff TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon. TAU is missorted and aggregated in an array of diseases known as tauopathies. Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications, changes of which affect microtubule stability and dynamics, microtubule interaction with other proteins and cellular structures, and mediate recruitment of microtubule-severing enzymes. As impairment of microtubule dynamics causes neuronal dysfunction, we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics. We therefore aimed to study the effects of a disease-causing mutation of TAU (P301L) on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics, to assess whether P301L-TAU causes stability-changing modifications to microtubules. To investigate TAU localization, phosphorylation, and effects on tubulin post-translational modifications, we expressed wild-type or P301L-TAU in human MAPT -KO induced pluripotent stem cell-derived neurons (iNeurons) and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU (pR5 mice). Human neurons expressing the longest TAU isoform (2N4R) with the P301L mutation showed increased TAU phosphorylation at the AT8, but not the p-Ser-262 epitope, and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons. P301L-TAU showed pronounced somatodendritic presence, but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU. P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation, but reduced acetylation, of microtubules compared with non-transgenic littermates. In sum, P301L-TAU results in changes in microtubule PTMs, suggestive of impairment of microtubule stability. This is accompanied by missorting and aggregation of TAU in mice but not in iNeurons. Microtubule PTMs/impairment may be of key importance in tauopathies.

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P301L-TAU对人类iPSC衍生皮质神经元和TAU转基因小鼠微管翻译后修饰的影响
摘要:TAU 是一种微管相关蛋白,可促进轴突中微管的组装和稳定性。在一系列被称为 tauopathies 的疾病中,TAU 会发生错构和聚集。微管对神经元功能至关重要,并通过一系列复杂的翻译后修饰(PTM)进行调节,这些修饰的变化会影响微管的稳定性和动力学、微管与其他蛋白质和细胞结构的相互作用,并介导微管破坏酶的招募。由于微管动力学损伤会导致神经元功能障碍,我们假设人类疾病中的认知障碍会受到微管动力学损伤的影响。因此,我们旨在研究 TAU 的致病突变(P301L)对指示微管稳定性和动力学的微管 PTMs 的水平和定位的影响,以评估 P301L-TAU 是否会导致微管的稳定性改变。为了研究TAU的定位、磷酸化以及对微管蛋白PTM的影响,我们在人类MAPT-KO诱导多能干细胞衍生神经元(iNeurons)中表达了野生型或P301L-TAU,并研究了转基因人类P301L-TAU的小鼠(pR5小鼠)海马神经元中的TAU。与表达内源性TAU的神经元相比,表达P301L突变的最长TAU异构体(2N4R)的人类神经元在AT8(而非p-Ser-262表位)处的TAU磷酸化增加,微管的多聚谷氨酰化和乙酰化增加。P301L-TAU显示出明显的体树突存在,但也成功地富集了轴突,其轴树突分布与外源表达的2N4R-野生型TAU相似。与非转基因小鼠相比,转基因小鼠中表达 P301L-TAU 的海马神经元表现出明显的错构化和 TAU 的典型 AT8 磷酸化,微管的多聚戊二酰化增加,但乙酰化减少。总之,P301L-TAU 导致微管 PTMs 发生变化,表明微管稳定性受损。与此同时,小鼠体内的TAU会发生错配和聚集,而iNeurons体内的TAU不会发生这种情况。微管PTMs/损伤可能是牛磺酸病的关键因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neural Regeneration Research
Neural Regeneration Research CELL BIOLOGY-NEUROSCIENCES
CiteScore
8.00
自引率
9.80%
发文量
515
审稿时长
1.0 months
期刊介绍: Neural Regeneration Research (NRR) is the Open Access journal specializing in neural regeneration and indexed by SCI-E and PubMed. The journal is committed to publishing articles on basic pathobiology of injury, repair and protection to the nervous system, while considering preclinical and clinical trials targeted at improving traumatically injuried patients and patients with neurodegenerative diseases.
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