Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice
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| Název: | Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice |
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| Autoři: | Stepan, Jens, Heinz, Daniel E, Dethloff, Frederik, Wiechmann, Svenja, Martinelli, Silvia, Hafner, Kathrin, Ebert, Tim, Junglas, Ellen, Häusl, Alexander S, Pöhlmann, Max L, Jakovcevski, Mira, Pape, Julius C, Zannas, Anthony S, Bajaj, Thomas, Hermann, Anke, Ma, Xiao, Pavenstädt, Hermann, Schmidt, Mathias V, Philipsen, Alexandra, Turck, Christoph W, Deussing, Jan M, Rammes, Gerhard, Robinson, Andrew C, Payton, Antony, Wehr, Michael C, Stein, Valentin, Murgatroyd, Christopher, Kremerskothen, Joachim, Kuster, Bernhard, Wotjak, Carsten T, Gassen, Nils C |
| Zdroj: | Stepan, J, Heinz, D E, Dethloff, F, Wiechmann, S, Martinelli, S, Hafner, K, Ebert, T, Junglas, E, Häusl, A S, Pöhlmann, M L, Jakovcevski, M, Pape, J C, Zannas, A S, Bajaj, T, Hermann, A, Ma, X, Pavenstädt, H, Schmidt, M V, Philipsen, A, Turck, C W, Deussing, J M, Rammes, G, Robinson, A C, Payton, A, Wehr, M C, Stein, V, Murgatroyd, C, Kremerskothen, J, Kuster, B, Wotjak, C T & Gassen, N C 2024, 'Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice', Science Signaling, vol. 17, no. 834, eadj6603. https://doi.org/10.1126/scisignal.adj6603 |
| Informace o vydavateli: | American Association for the Advancement of Science (AAAS), 2024. |
| Rok vydání: | 2024 |
| Témata: | Male, 0301 basic medicine, Hippocampus/metabolism, Neurons/metabolism, Hepatocyte Growth Factor/metabolism, Protein Serine-Threonine Kinases, 0601 Biochemistry and Cell Biology, Receptors, AMPA/metabolism, Hippocampus, Serine-Threonine Kinase 3, Memory/physiology, Tumor Suppressor Proteins/metabolism, Mice, 03 medical and health sciences, Memory, Alzheimer Disease, Animals, Humans, Protein Serine-Threonine Kinases/metabolism, Hippo Signaling Pathway, Receptors, AMPA, Phosphorylation, Neurons, 0303 health sciences, Neuronal Plasticity, Hepatocyte Growth Factor, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, Neuronal Plasticity/physiology, Phosphoproteins, Mice, Inbred C57BL, Alzheimer Disease/metabolism, Signal Transduction |
| Popis: | 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. |
| Druh dokumentu: | Article |
| Popis souboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 1937-9145 1945-0877 |
| DOI: | 10.1126/scisignal.adj6603 |
| Přístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/38687825 https://www.mendeley.com/catalogue/4eacf262-c45c-343f-af1e-2704e8090fa9/ https://doi.org/10.1126/scisignal.adj6603 http://www.scopus.com/inward/record.url?scp=85191930768&partnerID=8YFLogxK https://pure.manchester.ac.uk/ws/files/330820954/adj6603_ArticleContent_v12_1_.pdf https://research.manchester.ac.uk/en/publications/fec9abe7-5ca4-4800-89da-9efcc5895ede https://e-space.mmu.ac.uk/634615/ |
| Přístupové číslo: | edsair.doi.dedup.....b9ca457adee21719647f715bf5cc9444 |
| Databáze: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstrakt: | 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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| ISSN: | 19379145 19450877 |
| DOI: | 10.1126/scisignal.adj6603 |