Neuron-specific deamidation of translational repressor 4E-BP2 in postnatal brain

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Brain development, learning, memory, and perception rely on an intricate network of proteins that orchestrates higher cognitive functions of the human brain. An important biological process regulating the function of these molecules is protein synthesis, also termed translation. Translation controls the mechanisms regulating the strength of connection between neurons, a process called synaptic plasticity. Inhibition of translation blocks the formation of long-term memory and stimulation of translation promotes memory formation. Translation is a tightly regulated process. A key translational control pathway, regulated via the mTORC1 (mechanistic Target of Rapamycin Complex 1 (mTORC1)), is implicated in brain development, synaptic plasticity, learning, and memory. mTORC1 regulates translation in the brain via its major downstream target, 4E-binding protein 2 (4E-BP2). Recent studies have revealed that 4E-BP2 undergoes spontaneous brain-specific asparagine deamidation. However, the mechanisms underlying 4E-BP2 deamidation in the brain and the functional significance of this process remain unknown. Our preliminary data indicate that deamidated form of 4E-BP2 is less stable than wild-type form and its stability is increased in response to inhibition of mTORC1. Given that mTORC1 activity is reduced postnatally, this mechanism might explain the accumulation of deamidated 4E-BP2 during early postnatal brain development. Additionally, we found that translational landscape is altered when deamidated 4E-BP2 is overexpressed in neurons, suggesting that posttranslational modification of 4E-BP2 might regulate the output of mTORC1/4E-BP2 pathway and affect translation of mRNAs in the brain. In the proposed project, we will further investigate the mechanisms underlying 4E-BP2 deamidation and study its effect on brain functions. Specifically, we will generate genetically-modified mice expressing deamidated but not wild-type form of 4E-BP2, and study how neuronal activity and behaviours are affected. We will employ biochemical, electrophysiological, imaging and behavioral approaches to study the impact of 4E-BP2 deamidation on the brain during development and in adulthood. The proposed work will provide fundamental insights into the roles and mechanisms of 4E-BP2 deamidation, altogether advancing our understanding of how translational control shapes brain functions.