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Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1



Chalkiadaki, Kleanthi;

Hooshmandi, Mehdi;

Lach, Gilliard;

Statoulla, Elpida;

Simbriger, Konstanze;

Amorim, Ines S;

Kouloulia, Stella;

Gkogkas, Christos G; + view all

Chalkiadaki, Kleanthi;

Hooshmandi, Mehdi;

Lach, Gilliard;

Statoulla, Elpida;

Simbriger, Konstanze;

Amorim, Ines S;

Kouloulia, Stella;

Zafeiri, Maria;

Pothos, Panagiotis;

Bonneil, Éric;

Gantois, Ilse;

Popic, Jelena;

Kim, Sung-Hoon;

Wong, Calvin;

Cao, Ruifeng;

Komiyama, Noboru H;

Atlasi, Yaser;

Jafarnejad, Seyed Mehdi;

Khoutorsky, Arkady;

Gkogkas, Christos G;

– view fewer

(2022)

Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1.

Brain


10.1093/brain/awac398.

(In press).

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.

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