Chalkiadaki, Kleanthi;
Hooshmandi, Mehdi;
Lach, Gilliard;
Statoulla, Elpida;
Simbriger, Konstanze;
Amorim, Ines S;
Kouloulia, Stella;
... Gkogkas, Christos G; + view all
(2023)
Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1.
Brain
, Article awac398. 10.1093/brain/awac398.
(In press).
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Abstract
MAPK (mitogen-activated protein kinase) interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterised substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that whereas deletion of Mnk1/2 (Mnk DKO) impairs synaptic plasticity and memory in mice, ablation of phosho-eIF4E (Ser209) does not affect these processes, suggesting that Mnk1/2 possess additional downstream effectors in the brain. Translational profiling revealed only a small overlap between Mnk1/2- and phospho-eIF4E(Ser209)-regulated translatome. We identified the synaptic Ras GTPase activating protein 1 (Syngap1), encoded by a syndromic autism gene, as a downstream target of Mnk1 since Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk DKO mice. Knock-down of Syngap1 reversed memory deficits in Mnk DKO mice, and pharmacological inhibition of Mnks rescued autism-related phenotypes in Syngap1+/- mice. Thus, Syngap1 is a downstream effector of Mnk1, and the Mnks-Syngap1 axis regulates memory formation and autism-related behaviours.
| Type: | Article |
|---|---|
| Title: | Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1 |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/awac398 |
| Publisher version: | https://doi.org/10.1093/brain/awac398 |
| Language: | English |
| Additional information: | Copyright © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | autism, learning, memory, phosphorylation, synaptic translation, translational control |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10159367 |
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