Autism- and epilepsy-associated EEF1A2 mutations lead to translational dysfunction and altered actin bundling.

Muhaned S Mohamed, Eric Klann

Proceedings of the National Academy of Sciences of the United States of America 2023 Sep 19

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Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations of a neuron- and muscle-specific translation factor, eukaryotic Elongation Factor 1a2 (eEF1A2), which when mutated in patients results in autism, epilepsy, and intellectual disability. We characterize three EEF1A2 patient mutations, G70S, E122K, and D252H, and demonstrate that all three mutations decrease de novo protein synthesis and elongation rates in HEK293 cells. In mouse cortical neurons, the EEF1A2 mutations not only decrease de novo protein synthesis but also alter neuronal morphology, regardless of endogenous levels of eEF1A2, indicating that the mutations act via a toxic gain of function. We also show that eEF1A2 mutant proteins display increased tRNA binding and decreased actin-bundling activity, suggesting that these mutations disrupt neuronal function by decreasing tRNA availability and altering the actin cytoskeleton. More broadly, our findings are consistent with the idea that eEF1A2 acts as a bridge between translation and the actin cytoskeleton, which is essential for proper neuron development and function.

Citation

Muhaned S Mohamed, Eric Klann. Autism- and epilepsy-associated EEF1A2 mutations lead to translational dysfunction and altered actin bundling. Proceedings of the National Academy of Sciences of the United States of America. 2023 Sep 19;120(38):e2307704120