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Targeting upstream Hippo-pathway kinases releases the scaffolder WWC1 to promote synaptic plasticity and long-term memory in mice

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 hetero-protein complexes. However, genetic analysis suggests that the availability of WWC1 is constrained by its interaction with the Hippo kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction. A proteome-wide analysis of kinase inhibition in SH-SY5Y neuroblastoma cell line using the kinobead assay identified the upstream kinases MST1/2 as two major targets of the small molecule inhibitor XMU-MP1 (hereafter, MSTi)and Luteolin.Upon pharmacological inhibition of MST1/2 in male mice and human brain organoids WWC1 dissociated from LATS1/2, resulting in increased abundance of WWC1 in AMPAR complexes. Moreover, MSTi 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 ageing. Thus, blocking WWC1-LATS1/2 binding might be explored for development as cognitive enhancers.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Tim Ebert

LAB HEAD: Nils C Gassen

PROVIDER: PXD050351 | Pride | 2024-05-03

REPOSITORIES: Pride

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