tau 蛋白在阿尔茨海默病中破坏核质转运。
Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease.
机构信息
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Brain Science Institute, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
出版信息
Neuron. 2018 Sep 5;99(5):925-940.e7. doi: 10.1016/j.neuron.2018.07.039.
Abstract
Tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD), but the mechanism underlying tau-associated neural damage remains unclear. Here, we show that tau can directly interact with nucleoporins of the nuclear pore complex (NPC) and affect their structural and functional integrity. Pathological tau impairs nuclear import and export in tau-overexpressing transgenic mice and in human AD brain tissue. Furthermore, the nucleoporin Nup98 accumulates in the cell bodies of some tangle-bearing neurons and can facilitate tau aggregation in vitro. These data support the hypothesis that tau can directly interact with NPC components, leading to their mislocalization and consequent disruption of NPC function. This raises the possibility that NPC dysfunction contributes to tau-induced neurotoxicity in AD and tauopathies.
摘要
tau 是阿尔茨海默病（AD）中神经纤维缠结的主要成分，但 tau 相关神经损伤的机制仍不清楚。在这里，我们表明 tau 可以直接与核孔复合物（NPC）的核孔蛋白相互作用，并影响其结构和功能的完整性。病理性 tau 会损害在过表达 tau 的转基因小鼠和人类 AD 脑组织中的核输入和输出。此外，核孔蛋白 Nup98 会在一些携带缠结的神经元的细胞体中积累，并可以促进 tau 的体外聚集。这些数据支持 tau 可以直接与 NPC 成分相互作用，导致其定位错误和随后的 NPC 功能障碍的假说。这就提出了 NPC 功能障碍可能导致 AD 和 tau 病中 tau 诱导的神经毒性的可能性。
相似文献
1
Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease.tau 蛋白在阿尔茨海默病中破坏核质转运。
Neuron. 2018 Sep 5;99(5):925-940.e7. doi: 10.1016/j.neuron.2018.07.039.
2
Phospho-Tau Impairs Nuclear-Cytoplasmic Transport.磷酸化tau 蛋白可损害核质转运。
ACS Chem Neurosci. 2019 Jan 16;10(1):36-38. doi: 10.1021/acschemneuro.8b00632. Epub 2018 Nov 27.
3
Analysis of Tau/Nucleoporin Interactions by Surface Plasmon Resonance Spectroscopy.表面等离子体共振光谱分析 Tau/核孔蛋白相互作用。
Methods Mol Biol. 2023;2551:95-109. doi: 10.1007/978-1-0716-2597-2_8.
4
Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98.磷酸化而非寡聚化驱动核孔蛋白 Nup98 与 Tau 的积累。
Int J Mol Sci. 2022 Mar 23;23(7):3495. doi: 10.3390/ijms23073495.
5
Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in Alzheimer's disease.病理性 tau 驱动阿尔茨海默病神经元细胞质中核斑点支架蛋白 SRRM2 的异位积累。
Acta Neuropathol Commun. 2021 Jun 29;9(1):117. doi: 10.1186/s40478-021-01219-1.
6
Nuclear pore complex proteins in Alzheimer disease.阿尔茨海默病中的核孔复合体蛋白
J Neuropathol Exp Neurol. 2006 Jan;65(1):45-54. doi: 10.1097/01.jnen.0000195939.40410.08.
7
Cholesterol and tau protein--findings in Alzheimer's and Niemann Pick C's disease.胆固醇与tau蛋白——阿尔茨海默病和尼曼匹克C病的研究发现。
Pharmacopsychiatry. 2003 Sep;36 Suppl 2:S120-6. doi: 10.1055/s-2003-43060.
8
Tau-FG-nucleoporin98 interaction and impaired nucleocytoplasmic transport in Alzheimer's disease.Tau蛋白与FG核孔蛋白98的相互作用及阿尔茨海默病中核质运输受损
Brief Funct Genomics. 2023 Apr 13;22(2):161-167. doi: 10.1093/bfgp/elac022.
9
AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer's disease and other tauopathies.在阿尔茨海默病和其他 tau 病患者的缠结和前缠结神经元中，AMPK 异常激活。
Acta Neuropathol. 2011 Mar;121(3):337-49. doi: 10.1007/s00401-010-0759-x. Epub 2010 Oct 19.
10
Tau Ser208 phosphorylation promotes aggregation and reveals neuropathologic diversity in Alzheimer's disease and other tauopathies.tau 丝氨酸 208 位磷酸化促进聚集，并揭示阿尔茨海默病和其他 tau 病中的神经病理学多样性。
Acta Neuropathol Commun. 2020 Jun 22;8(1):88. doi: 10.1186/s40478-020-00967-w.
引用本文的文献
1
A phenotypic screen for novel small molecules that correct tau-mediated pathologies in human frontotemporal dementia neurons.针对可纠正人类额颞叶痴呆神经元中tau介导病理的新型小分子进行的表型筛选。
Alzheimers Dement. 2025 Sep;21(9):e70620. doi: 10.1002/alz.70620.
2
Axonal tau reduction ameliorates tau and amyloid pathology in a mouse model of Alzheimer's disease.轴突tau蛋白减少可改善阿尔茨海默病小鼠模型中的tau蛋白和淀粉样蛋白病理。
Transl Neurodegener. 2025 Jul 29;14(1):39. doi: 10.1186/s40035-025-00499-0.
3
Phase Separation Regulates Metabolism, Mitochondria, and Diseases.相分离调节新陈代谢、线粒体及疾病。
MedComm (2020). 2025 Jul 1;6(7):e70283. doi: 10.1002/mco2.70283. eCollection 2025 Jul.
4
The expanding repertoire of ESCRT functions in cell biology and disease.ESCRT功能在细胞生物学和疾病中的不断扩展
Nature. 2025 Jun 25. doi: 10.1038/s41586-025-08950-y.
5
Polymeric Giant Unilamellar Vesicles Support Longevity of Native Nuclei in Protocells.聚合巨型单层囊泡支持原始细胞中天然细胞核的寿命。
Small Sci. 2025 Mar 18;5(6):2400622. doi: 10.1002/smsc.202400622. eCollection 2025 Jun.
6
Ubiquitin-Proteasome System Dysregulation in Alzheimer's Disease Impacts Protein Abundance.阿尔茨海默病中泛素-蛋白酶体系统失调影响蛋白质丰度。
bioRxiv. 2025 May 29:2025.05.29.656728. doi: 10.1101/2025.05.29.656728.
7
Comparisons of efficacy and safety of immunotherapies for Alzheimer's disease treatment: A network meta-analysis of randomised controlled trials.阿尔茨海默病治疗免疫疗法的疗效和安全性比较：随机对照试验的网状Meta分析
Clin Med (Lond). 2025 Jun 3;25(4):100336. doi: 10.1016/j.clinme.2025.100336.
8
The many connections of UFMylation with Alzheimer's disease: a comprehensive review.泛素样修饰与阿尔茨海默病的多种联系：综述
Mol Neurodegener. 2025 Jun 4;20(1):66. doi: 10.1186/s13024-025-00855-8.
9
The nuclear envelope and nuclear pore complexes in neurodegenerative diseases.神经退行性疾病中的核膜与核孔复合体
Front Cell Dev Biol. 2025 May 13;13:1550859. doi: 10.3389/fcell.2025.1550859. eCollection 2025.
10
Tau-targeting nanoparticles for treatment of Alzheimer's disease.用于治疗阿尔茨海默病的靶向tau蛋白纳米颗粒。
Exploration (Beijing). 2024 Jun 21;5(2):20230137. doi: 10.1002/EXP.20230137. eCollection 2025 Apr.
本文引用的文献
1
Stress Granule Assembly Disrupts Nucleocytoplasmic Transport.应激颗粒组装破坏核质转运。
Cell. 2018 May 3;173(4):958-971.e17. doi: 10.1016/j.cell.2018.03.025. Epub 2018 Apr 5.
2
Dysregulation of RNA Binding Protein Aggregation in Neurodegenerative Disorders.神经退行性疾病中RNA结合蛋白聚集的失调
Front Mol Neurosci. 2017 Apr 4;10:89. doi: 10.3389/fnmol.2017.00089. eCollection 2017.
3
Mutant Huntingtin Disrupts the Nuclear Pore Complex.突变型亨廷顿蛋白破坏核孔复合体。
Neuron. 2017 Apr 5;94(1):93-107.e6. doi: 10.1016/j.neuron.2017.03.023.
4
Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport.聚谷氨酰胺扩展的亨廷顿蛋白加剧了与年龄相关的核完整性破坏和核质运输紊乱。
Neuron. 2017 Apr 5;94(1):48-57.e4. doi: 10.1016/j.neuron.2017.03.027.
5
Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes.FUS和SFPQ功能丧失导致的Tau异构体比例改变引发类似额颞叶痴呆的表型。
Cell Rep. 2017 Jan 31;18(5):1118-1131. doi: 10.1016/j.celrep.2017.01.013.
6
Simple rules for passive diffusion through the nuclear pore complex.通过核孔复合体进行被动扩散的简单规则。
J Cell Biol. 2016 Oct 10;215(1):57-76. doi: 10.1083/jcb.201601004. Epub 2016 Oct 3.
7
Simple biophysics underpins collective conformations of the intrinsically disordered proteins of the Nuclear Pore Complex.简单的生物物理学是核孔复合体内在无序蛋白质集体构象的基础。
Elife. 2016 May 20;5:e10785. doi: 10.7554/eLife.10785.
8
Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity.tau蛋白与RNA结合蛋白TIA1的相互作用调节tau蛋白的病理生理学和毒性。
Cell Rep. 2016 May 17;15(7):1455-1466. doi: 10.1016/j.celrep.2016.04.045. Epub 2016 May 6.
9
The Multiple Faces of Disordered Nucleoporins.核孔蛋白紊乱的多种表现形式。
J Mol Biol. 2016 May 22;428(10 Pt A):2011-24. doi: 10.1016/j.jmb.2016.01.002. Epub 2016 Jan 11.
10
Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer's disease brain.源自阿尔茨海默病大脑的一种罕见磷酸化高分子量tau蛋白的神经元摄取与传播。
Nat Commun. 2015 Oct 13;6:8490. doi: 10.1038/ncomms9490.
Zotero 插件