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糖原合成酶激酶3β磷酸化催化tau聚集成阿尔茨海默病样细丝。

GSK3β phosphorylation catalyzes the aggregation of tau into Alzheimer's disease-like filaments.

作者信息

Chakraborty Pijush, Ibáñez de Opakua Alain, Purslow Jeffrey A, Fromm Simon A, Chatterjee Debdeep, Zachrdla Milan, Zhuang Shannon, Puri Sambhavi, Wolozin Benjamin, Zweckstetter Markus

机构信息

Department for NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Göttingen 37077, Germany.

German Center for Neurodegenerative Diseases, Göttingen 37075, Germany.

出版信息

Proc Natl Acad Sci U S A. 2024 Dec 24;121(52):e2414176121. doi: 10.1073/pnas.2414176121. Epub 2024 Dec 18.

DOI:10.1073/pnas.2414176121
PMID:39693350
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11670061/
Abstract

The pathological deposition of proteins is a hallmark of several devastating neurodegenerative diseases. These pathological deposits comprise aggregates of proteins that adopt distinct structures named strains. However, the molecular factors responsible for the formation of distinct aggregate strains are unknown. Here, we show that the serine/threonine kinase GSK3β catalyzes the aggregation of the protein tau into Alzheimer's disease (AD)-like filaments. We demonstrate that phosphorylation by GSK3β, but not by several other kinases, promotes the aggregation of full-length tau as well as enhances phase separation into gel-like condensate structures. Cryoelectron microscopy further reveals that the fibrils formed by GSK3β-phosphorylated tau adopt a fold comparable to that of paired helical filaments isolated from the brains of AD patients. Our results elucidate the intricate relationship between posttranslational modification and the formation of tau strains in neurodegenerative diseases.

摘要

蛋白质的病理性沉积是几种毁灭性神经退行性疾病的标志。这些病理性沉积物由蛋白质聚集体组成，这些聚集体具有名为毒株的独特结构。然而，负责形成不同聚集体毒株的分子因素尚不清楚。在这里，我们表明丝氨酸/苏氨酸激酶GSK3β催化蛋白质tau聚集成阿尔茨海默病（AD）样细丝。我们证明，GSK3β而非其他几种激酶的磷酸化促进全长tau的聚集，并增强相分离形成凝胶状凝聚结构。冷冻电子显微镜进一步揭示，由GSK3β磷酸化的tau形成的原纤维具有与从AD患者大脑中分离出的双螺旋细丝相当的折叠结构。我们的结果阐明了翻译后修饰与神经退行性疾病中tau毒株形成之间的复杂关系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4802/11670061/55096ace781e/pnas.2414176121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4802/11670061/57798bd3798c/pnas.2414176121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4802/11670061/0d35410db84e/pnas.2414176121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4802/11670061/fedf1496c6f3/pnas.2414176121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4802/11670061/66574f5ad9be/pnas.2414176121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4802/11670061/55096ace781e/pnas.2414176121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4802/11670061/57798bd3798c/pnas.2414176121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4802/11670061/0d35410db84e/pnas.2414176121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4802/11670061/fedf1496c6f3/pnas.2414176121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4802/11670061/66574f5ad9be/pnas.2414176121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4802/11670061/55096ace781e/pnas.2414176121fig05.jpg

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Cryo-EM structures of tau filaments from SH-SY5Y cells seeded with brain extracts from cases of Alzheimer's disease and corticobasal degeneration.源自阿尔茨海默病和皮质基底节变性病例脑提取物接种的 SH-SY5Y 细胞中的 tau 丝状体的冷冻电镜结构。
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Biomolecular condensates can both accelerate and suppress aggregation of α-synuclein.
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