Special LMNN Seminar // Translation regulation in Neurodegenerative diseases: What we know about elongation factor-2 kinase (eEF2K) in Alzheimer’s disease.

mRNA translation and protein synthesis at synapses are tightly coupled to synaptic activity, and play an essential role in the long lasting forms of synaptic plasticity. A key molecule regulating dendritic mRNA translation is the calcium/Calmodulin dependent elongation factor-2 kinase (eEF2K), which is activated in response to glutamatergic neurotransmission. During this presentation, I will describe some recent literature, including our own published data, on the relevance of eEF2K to Alzheimer’s disease neuropathology. We have found that eEF2K inhibition blocks the toxicity of amyloid-β (Aβ) oligomers in neuronal cultures by activating Nuclear factor erythroid-derived 2-like 2 (NRF2), a master regulator of antioxidant response. Furthermore, in the transgenic APP/PS1 mice of cerebral Aβ amyloidosis, eEF2K activity is particularly increased in the granule cell layer (GCL) neurons of the hippocampal dentate gyrus, implicating eEF2K activity in the adult neurogenesis. Our recent data indicate that aberrant eEF2K activity is also relevant to neuropathology of Parkinson disease and motor neurone disease. Various experimental approaches, including genome editing by CRISPR/Cas9, to target eEF2K in pre-clinical rodent models will also be discussed.