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

Kleanthi Chalkiadaki; Mehdi Hooshmandi; Gilliard Lach; Elpida Statoulla; Konstanze Simbriger; Ines S. Amorim; Stella Kouloulia; Maria Zafeiri; Panagiotis Pothos; Éric Bonneil; Ilse Gantois; Jelena Popic; Sung-Hoon Kim; Calvin Wong; Ruifeng Cao; Noboru H. Komiyama; Yaser Atlasi; Seyed Mehdi Jafarnejad; Arkady Khoutorsky; Christos G. Gkogkas

doi:10.1093/brain/awac398

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

Kleanthi Chalkiadaki, Mehdi Hooshmandi, Gilliard Lach, Elpida Statoulla, Konstanze Simbriger^*, Ines S. Amorim, Stella Kouloulia^*, Maria Zafeiri, Panagiotis Pothos, Éric Bonneil, Ilse Gantois, Jelena Popic, Sung-Hoon Kim, Calvin Wong, Ruifeng Cao, Noboru H. Komiyama, Yaser Atlasi, Seyed Mehdi Jafarnejad, Arkady Khoutorsky, Christos G. Gkogkas^*

^*Corresponding author for this work

School of Medicine, Dentistry and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

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Abstract

MAPK interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterized substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that, whereas deletion of Mnk1/2 (Mnk double knockout) impairs synaptic plasticity and memory in mice, ablation of phospho-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 the 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 because Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk double knockout mice. Knockdown of Syngap1 reversed memory deficits in Mnk double knockout 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.

Original language	English
Pages (from-to)	2175-2190
Number of pages	16
Journal	Brain
Volume	146
Issue number	5
Early online date	31 Oct 2022
DOIs	https://doi.org/10.1093/brain/awac398
Publication status	Published - 01 May 2023

Keywords

autism
learning
memory
phosphorylation
synaptic translation
translational control
Neurology (clinical)

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Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1
Copyright 2022 The Authors. Published by Oxford University Press on behalf of the Guarantors of Brain. This work is made available online in accordance with the publisher’s policies. Please refer to any applicable terms of use of the publisher.
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Chalkiadaki, K., Hooshmandi, M., Lach, G., Statoulla, E., Simbriger, K., Amorim, I. S., Kouloulia, S., Zafeiri, M., Pothos, P., Bonneil, É., Gantois, I., Popic, J., Kim, S.-H., Wong, C., Cao, R., Komiyama, N. H., Atlasi, Y., Jafarnejad, S. M., Khoutorsky, A., & Gkogkas, C. G. (2023). Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1. Brain, 146(5), 2175-2190. https://doi.org/10.1093/brain/awac398

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title = "Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1",

abstract = "MAPK interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterized substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that, whereas deletion of Mnk1/2 (Mnk double knockout) impairs synaptic plasticity and memory in mice, ablation of phospho-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 the 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 because Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk double knockout mice. Knockdown of Syngap1 reversed memory deficits in Mnk double knockout 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.",

keywords = "autism, learning, memory, phosphorylation, synaptic translation, translational control, Neurology (clinical)",

author = "Kleanthi Chalkiadaki and Mehdi Hooshmandi and Gilliard Lach and Elpida Statoulla and Konstanze Simbriger and Amorim, {Ines S.} and Stella Kouloulia and Maria Zafeiri and Panagiotis Pothos and {\'E}ric Bonneil and Ilse Gantois and Jelena Popic and Sung-Hoon Kim and Calvin Wong and Ruifeng Cao and Komiyama, {Noboru H.} and Yaser Atlasi and Jafarnejad, {Seyed Mehdi} and Arkady Khoutorsky and Gkogkas, {Christos G.}",

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month = may,

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doi = "10.1093/brain/awac398",

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Chalkiadaki, K, Hooshmandi, M, Lach, G, Statoulla, E, Simbriger, K, Amorim, IS, Kouloulia, S, Zafeiri, M, Pothos, P, Bonneil, É, Gantois, I, Popic, J, Kim, S-H, Wong, C, Cao, R, Komiyama, NH, Atlasi, Y , Jafarnejad, SM, Khoutorsky, A & Gkogkas, CG 2023, 'Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1', Brain, vol. 146, no. 5, pp. 2175-2190. https://doi.org/10.1093/brain/awac398

TY - JOUR

T1 - Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1

AU - Chalkiadaki, Kleanthi

AU - Hooshmandi, Mehdi

AU - Lach, Gilliard

AU - Statoulla, Elpida

AU - Simbriger, Konstanze

AU - Amorim, Ines S.

AU - Kouloulia, Stella

AU - Zafeiri, Maria

AU - Pothos, Panagiotis

AU - Bonneil, Éric

AU - Gantois, Ilse

AU - Popic, Jelena

AU - Kim, Sung-Hoon

AU - Wong, Calvin

AU - Cao, Ruifeng

AU - Komiyama, Noboru H.

AU - Atlasi, Yaser

AU - Jafarnejad, Seyed Mehdi

AU - Khoutorsky, Arkady

AU - Gkogkas, Christos G.

PY - 2023/5/1

Y1 - 2023/5/1

N2 - MAPK interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterized substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that, whereas deletion of Mnk1/2 (Mnk double knockout) impairs synaptic plasticity and memory in mice, ablation of phospho-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 the 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 because Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk double knockout mice. Knockdown of Syngap1 reversed memory deficits in Mnk double knockout 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.

AB - MAPK interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterized substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that, whereas deletion of Mnk1/2 (Mnk double knockout) impairs synaptic plasticity and memory in mice, ablation of phospho-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 the 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 because Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk double knockout mice. Knockdown of Syngap1 reversed memory deficits in Mnk double knockout 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.

KW - autism

KW - learning

KW - memory

KW - phosphorylation

KW - synaptic translation

KW - translational control

KW - Neurology (clinical)

U2 - 10.1093/brain/awac398

DO - 10.1093/brain/awac398

M3 - Article

C2 - 36315645

SN - 0006-8950

VL - 146

SP - 2175

EP - 2190

JO - Brain

JF - Brain

IS - 5

ER -

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

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Keywords

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