| Autor: |
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 |
| Předmět: |
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| Zdroj: |
Brain: A Journal of Neurology; May2023, Vol. 146 Issue 5, p2175-2190, 16p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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