Twin Brain Enzymes With Opposite Jobs: MNK1 and MNK2 Diverge at the Synapse

Two enzymes can be nearly identical in structure and still do entirely different jobs. That is what a research team at the Max Delbruck Center for Molecular Medicine has established for MNK1 and MNK2, a pair of kinases that both regulate how cells manufacture proteins - but that, in the brain, appear to govern separate aspects of behavior and cognition.

The findings, published in Molecular Psychiatry, have direct implications for drug development. MNK kinases have attracted substantial interest as drug targets for nervous system disorders and chronic pain. Whether a drug that inhibits both would be equivalent to one targeting only MNK1, or only MNK2, had been an open question. The new work suggests the difference matters considerably.

Object Memory Versus Social Behavior

The team, led by doctoral student Rosalba Olga Proce in the Molecular and Cellular Basis of Behavior lab of Dr. Hanna Hornberg, used genetically engineered mice in which either the MNK1 or the MNK2 gene had been knocked out. The behavioral differences were clear and specific.

Mice lacking MNK1 showed reduced interest in newly introduced objects compared to controls, and their memory of those objects was impaired. Mice lacking MNK2 performed normally on object recognition tests. But those same MNK2-knockout mice showed enhanced interest in social contacts - a shift in behavior that mice without MNK1 did not display.

"The behavioral differences we observed suggest that each kinase has a specialized function," said Proce. "It might be preferable to target each kinase individually when designing drugs."

The Molecular Differences Are Most Visible at Synapses

To understand what drives these behavioral differences, the team combined large-scale molecular analyses with the behavioral testing. They applied proteomics (measuring protein levels), transcriptomics (measuring gene expression), and phosphoproteomics (measuring which proteins have been chemically activated by phosphate groups) to cerebral cortex tissue from both types of knockout mice.

Mice without MNK1 had an abundance of ribosomal proteins - the molecular machinery responsible for translating messenger RNA into working proteins. By contrast, in mice without MNK2, the expression and phosphorylation of proteins that transmit signals at synapses was reduced.

The most striking finding was where the differences were concentrated. When the team looked specifically at synapses rather than whole-brain samples, the molecular distinctions between the two kinase knockouts were far more pronounced. This was not what the researchers expected.

"We were surprised to see these differences," said Hornberg. "This suggests that the kinases may have different functions in the cell body compared to synapses."

Protein Synthesis at Synapses - Why It Matters for Learning

Synaptic protein synthesis occupies a central role in learning and memory. When a synapse is repeatedly activated - as happens during learning - local production of new proteins strengthens the connection between the two neurons. This process, called synaptic plasticity, is the cellular basis for how the brain rewires itself in response to experience.

The fact that MNK1 and MNK2 appear to influence synaptic protein synthesis through different mechanisms suggests they occupy distinct positions in this process. MNK1's apparent role in regulating ribosomal protein abundance could affect the overall translational capacity of synapses. MNK2's influence on signaling protein phosphorylation, by contrast, could alter how quickly or strongly a synapse responds to incoming signals.

Both kinases target a protein called eIF4E, a translation initiation factor that sits at a key regulatory checkpoint for protein synthesis. Earlier research had suggested that phosphorylating eIF4E was the primary job of both kinases. The new data complicate that picture by showing that the downstream effects in neurons diverge substantially.

Toward More Selective Therapies - With Important Caveats

The study used mouse models, which do not always translate directly to human neurology. The behavioral tests - object recognition and social interaction - are standard measures in preclinical neuroscience but capture only a narrow slice of the cognitive and behavioral complexity relevant to human neurological disorders. Differences in how MNK1 and MNK2 function in primate brains, where synaptic organization is more elaborate, remain to be explored.

What the study does provide is a clearer rationale for developing kinase-selective inhibitors rather than compounds that block both enzymes simultaneously. If MNK1 inhibition primarily affects memory-like functions and MNK2 inhibition affects social behavior, a drug designed for one indication might inadvertently disrupt the other.

The team now aims to identify the other molecular partners with which MNK1 and MNK2 interact, and to examine in greater detail how the two kinases regulate messenger RNA translation during synaptic plasticity. By building a more complete map of the kinases' respective protein networks, the researchers hope to lay the groundwork for more precise interventions in neurological and psychiatric conditions.