Specificity of the MAP kinase-interacting kinases MNK1 and MNK2 in synaptic plasticity and function

• Applicant: Hanna Hoernberg, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565656382

Learning and memory rely on plastic connections between synapses. To modulate synaptic function and form stable memories, a necessary step is making new proteins. Synaptic protein production is tightly controlled, and when this process goes wrong, it can lead to a range of brain disorders, including Alzheimer's, autism, and chronic pain. Therefore, understanding the mechanisms that regulate synaptic protein production is an important first step to developing new treatment approaches for these disorders. The serine/threonine kinases mitogen-activated protein kinase (MAPK) interacting protein kinases 1 and 2 (MNK 1 and 2) are two kinases that modulate the translation of mRNAs into proteins through phosphorylation of the eucaryotic initiation factor 4E. As eIF4E-mediated translation plays an important role in synaptic plasticity, the MNKs have emerged as interesting drug targets for nervous system disorders that affect translation. In the brain, the MNKs are expressed in overlapping neuronal populations, but their individual function is poorly understood. To further develop the MNKs as drug targets, understanding the functional specialization of the MNK proteins is essential. This project aims to identify the individual roles of MNK1 and MNK2 in neuronal and synaptic function. Our previous work has shown that in mice, deletion of either MNK1 or MNK2 has fundamentally different effects on the proteins located at the synapse - the synaptic proteome - and these differences are reflected by distinct behavioral symptoms in MNK1 and MNK2 knockout mice. Based on these results, we hypothesize that MNK1 and MNK2 regulate distinct aspects of synaptic function by modulating different pools of mRNA via separate mechanisms. We will examine this hypothesis using a combination of synapse-specific mass spectrometry, ribosome profiling, and confocal and electron microscopy in MNK1 and MNK2 knockout mice. Specifically, we will (i) decipher the neuronal upstream modulators and downstream targets of MNK1 and MNK2, (ii) determine the specific roles of the MNKs in synaptic formation and function, and (iii) examine how MNK1 and MNK2 regulate activity-dependent synaptic translation. In summary, this project will deliver fundamental insight into how the MNK proteins regulate separate aspects of neuronal functions. The results will advance our understanding of how synaptic protein translation is regulated, and may uncover targeted approaches to treat neurological conditions affecting translation.

• DFG Programme: Research Grants