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

• Published in: Science signaling 2024-04, Vol.17 (834), p.eadj6603
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Animal models; Animals; Cognition; Cognitive ability; Glutamate receptors; Hepatocyte Growth Factor - metabolism; Hippo Signaling Pathway; Hippocampus; Hippocampus - metabolism; Humans; Intracellular Signaling Peptides and Proteins; Kinases; Long term memory; Male; Memory; Memory - physiology; Mice; Mice, Inbred C57BL; Neurodegenerative diseases; Neuronal Plasticity - physiology; Neurons - metabolism; Phosphoproteins; Phosphorylation; Plasticity; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Scaffolding; Serine-Threonine Kinase 3; Signal Transduction; Synaptic plasticity; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 1945-0877; 1937-9145; 1937-9145
• DOI: 10.1126/scisignal.adj6603

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.