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化学合成揭示了O-糖基化在微管相关蛋白Tau中的致病作用。

Chemical Synthesis Reveals Pathogenic Role of -Glycosylation in Microtubule-Associated Protein Tau.

作者信息

Powell Wyatt C, Jing Ruiheng, Herlory Morgane, Holland Patrick, Poliyenko Darya, Ebmeier Christopher C, Stowell Michael H B, Walczak Maciej A

机构信息

Department of Chemistry, University of Colorado, Boulder, Colorado 80309, United States.

Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, United States.

出版信息

J Am Chem Soc. 2025 Feb 26;147(8):6995-7007. doi: 10.1021/jacs.4c17873. Epub 2025 Feb 17.

DOI:10.1021/jacs.4c17873
PMID:39959999
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11892074/
Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of tau protein aggregates. In this study, we investigated the effects of -glycosylation on tau, focusing on its impact on aggregation and phase behavior. We chemically prepared homogeneous glycoproteins with high-mannose glycans or a single -acetylglucosamine at the confirmed glycosylation sites in K18 and 2N4R tau. Our findings reveal that -glycosylation significantly alters biophysical properties and potentially cellular functions of tau. Small glycans promote tau aggregation and liquid-liquid phase separation (LLPS), while larger glycans reduce these effects. High mannose glycans at N410 enhance phosphorylation by GSK3β, suggesting a pathological role in AD. Functional assays demonstrate that -glycosylation does not impact microtubule polymerization dynamics but modulates aggregation kinetics and morphology. This research underscores the importance of glycosylation in tau pathology and opens new avenues for therapeutic interventions targeting glycan processing.

摘要

阿尔茨海默病（AD）是一种以tau蛋白聚集体积累为特征的神经退行性疾病。在本研究中，我们研究了O-糖基化对tau的影响，重点关注其对聚集和相行为的影响。我们在K18和2N4R tau的已确认糖基化位点化学制备了具有高甘露糖聚糖或单个N-乙酰葡糖胺的均一糖蛋白。我们的研究结果表明，O-糖基化显著改变了tau的生物物理性质和潜在的细胞功能。小聚糖促进tau聚集和液-液相分离（LLPS），而大聚糖则减少这些影响。N410处的高甘露糖聚糖增强了GSK3β介导的磷酸化，提示其在AD中的病理作用。功能分析表明，O-糖基化不影响微管聚合动力学，但调节聚集动力学和形态。本研究强调了糖基化在tau病理学中的重要性，并为靶向聚糖加工的治疗干预开辟了新途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca63/11892074/32137f3ad848/nihms-2058974-f0008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca63/11892074/37152c2cc1d8/nihms-2058974-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca63/11892074/22d462af96e8/nihms-2058974-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca63/11892074/32137f3ad848/nihms-2058974-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca63/11892074/60eacfa011dc/nihms-2058974-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca63/11892074/af0cc00fa734/nihms-2058974-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca63/11892074/37152c2cc1d8/nihms-2058974-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca63/11892074/22d462af96e8/nihms-2058974-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca63/11892074/32137f3ad848/nihms-2058974-f0008.jpg

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本文引用的文献

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ACS Cent Sci. 2024 Nov 13;10(11):2145-2161. doi: 10.1021/acscentsci.4c01319. eCollection 2024 Nov 27.
2
Human brain glycoform coregulation network and glycan modification alterations in Alzheimer's disease.人类大脑糖型核心调控网络与阿尔茨海默病中的聚糖修饰改变。
Sci Adv. 2024 Apr 5;10(14):eadk6911. doi: 10.1126/sciadv.adk6911.
3
Mutations in Tau Protein Promote Aggregation by Favoring Extended Conformations.Tau蛋白突变通过促进伸展构象来促进聚集。
JACS Au. 2023 Dec 19;4(1):92-100. doi: 10.1021/jacsau.3c00550. eCollection 2024 Jan 22.
4
Novel avenues of tau research.tau 研究的新途径。
Alzheimers Dement. 2024 Mar;20(3):2240-2261. doi: 10.1002/alz.13533. Epub 2024 Jan 3.
5
A closer look at amyloid ligands, and what they tell us about protein aggregates.深入研究淀粉样蛋白配体，以及它们向我们揭示的关于蛋白质聚集物的信息。
Chem Soc Rev. 2024 Feb 5;53(3):1354-1374. doi: 10.1039/d3cs00518f.
6
Tau-targeting therapies for Alzheimer disease: current status and future directions.针对阿尔茨海默病的靶向 Tau 治疗：现状与未来方向。
Nat Rev Neurol. 2023 Dec;19(12):715-736. doi: 10.1038/s41582-023-00883-2. Epub 2023 Oct 24.
7
Chemical Synthesis of Microtubule-Associated Protein Tau.微管相关蛋白 Tau 的化学合成。
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