Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling Pub Date : 2024-04-30 DOI:10.1126/scisignal.adj6603

Jens Stepan, Daniel E. Heinz, Frederik Dethloff, Svenja Wiechmann, Silvia Martinelli, Kathrin Hafner, Tim Ebert, Ellen Junglas, Alexander S. Häusl, Max L. Pöhlmann, Mira Jakovcevski, Julius C. Pape, Anthony S. Zannas, Thomas Bajaj, Anke Hermann, Xiao Ma, Hermann Pavenstädt, Mathias V. Schmidt, Alexandra Philipsen, Christoph W. Turck, Jan M. Deussing, Gerhard Rammes, Andrew C. Robinson, Antony Payton, Michael C. Wehr, Valentin Stein, Christopher Murgatroyd, Joachim Kremerskothen, Bernhard Kuster, Carsten T. Wotjak, Nils C. Gassen

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引用次数: 0

Abstract

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer’s disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.

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抑制 Hippo 通路激酶释放 WWC1，促进小鼠的 AMPAR 依赖性突触可塑性和长期记忆

突触后 AMPA 型谷氨酸受体（AMPAR）的定位、数量和功能对突触可塑性至关重要，而突触可塑性是学习和记忆的细胞相关性。Hippo 通路成员 WWC1 是含 AMPAR 蛋白复合物的重要组成部分。然而，WWC1 的可用性受到其与 Hippo 通路激酶 LATS1 和 LATS2（LATS1/2）相互作用的限制。在这里，我们探索了这种相互作用的生化调控，并发现它在体内可作为药理靶点。在原发性海马神经元中，上游激酶 MST1 和 MST2（MST1/2）对 LATS1/2 的磷酸化增强了 WWC1 和 LATS1/2 之间的相互作用，从而封闭了 WWC1。对雄性小鼠和人类脑源性器官组织中的 MST1/2 进行药理抑制，可促进 WWC1 与 LATS1/2 的分离，从而增加含 AMPAR 复合物中的 WWC1。抑制 MST1/2 可增强小鼠海马脑切片的突触传递，改善健康雄性小鼠以及阿尔茨海默病和衰老雄性小鼠模型的认知能力。因此，破坏 WWC1 和 LATS1/2 之间相互作用的化合物可作为认知增强剂进行开发。

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

Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY

CiteScore

9.50

自引率

0.00%

发文量

148

审稿时长

3-8 weeks

期刊介绍： "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.