Christos Gkogkas

Dr Christos Gkogkas is a Chancellor’s Fellow at the Patrick Wild Centre and The University of Edinburgh’s Centre for Discovery Brain Sciences.

The human brain is like a finely tuned orchestra, which is dependent on trillions of interactions between neurons or nerve cells. These interactions are called synaptic connections. Synaptic function depends on the synthesis of proteins carrying out various functions.

Increased eIF4E phopshorylation in the hippocampus of Fragile X syndrome (FXS) model mice (Fmr1-/y). Phopshorylation of eIF4E (eukaryotic initiation factor 4E) downstream of the Ras/MAPK pathway stimulates protein synthesis initiation. In FXS, protein synthesis is elevated in the hippocampus and cortex. Using phosphomutant mice (Eif4eKi) to effectively reduce eIF4E phosphorylation, we achieved reversal of autism-like behaviours (social interaction, repetitive behaviours) in Fmr1 -/y mice. Similarly, a compound blocking the kinase (Mnk), which pshosphorylates eIF4E achieved rescue of autism-like behaviours in the Fmr1-/y mous emodels of FXS. NeuN is a biomarker of neurons, DRAQ5 a marker for DNA integrity, both used to quantify changes in phospho-eIF4E.

My lab is interested in understanding the molecular mechanisms regulating protein synthesis in the brain and how these molecular mechanisms control complex brain functions and behaviours, such as learning, memory, social interactions, anxiety and fear.

Dysregulated protein synthesis is behind several disorders co-diagnosed with highrates of autism, such as fragile X syndrome, tuberous sclerosis and PTEN hamartomas with autism.

Moreover, mutations in protein synthesis factors — for instance eIF4E — have been identified in boys diagnosed with classical autism. Therefore, altered protein synthesis can induce changes in synaptic proteins and in turn affect connections between neurons.

During my postdoctoral training I was the first to show that dysregulated initiation of protein synthesis engenders autism-like behaviours in rodents. I proposed the use of protein synthesis initiation inhibitors as a potential therapeutic avenue for autism spectrum disorders and other neuropsychiatric diseases.


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