The 4E-BPs as Translational Regulators in Neurological Disorders: Molecular Mechanisms and Therapeutic Potential.

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Protein translation is essential for maintaining the optimal functioning of the human nervous system. The 4E-Binding proteins (4E-BPs) are central regulators of this process, acting on the initiation factor eIF4E. Three homologs 4E-BP1, 4E-BP2, and 4E-BP3, are differentially expressed, with the phosphorylation state controlling cap-dependent translation in response to diverse physiological inputs, including growth factors, cytokines, hormones, nutrient availability, and signaling cascades converging on kinases such as mTOR. Dysregulation of 4E-BP activity has been implicated in multiple disease contexts, including neurodegenerative disorders (e.g., Parkinson's disease, Alzheimer's disease), neurodevelopmental disorders (e.g., Autism spectrum disorder, Epilepsy), neuropsychiatric conditions (e.g., Depression, Schizophrenia), and autoimmune diseases (e.g., Multiple sclerosis, Guillain-Barré syndrome). We aim to explore the importance of 4E-BPs through a neurological perspective and understand their role as therapeutic targets. In this review, we provide a comprehensive analysis of the three 4E-BP homologs in the central nervous system, emphasizing the CNS-specific dominance of 4E-BP2 and its link to synaptic plasticity and cognitive function. We further examine and provide mechanistic insights into how 4E-BPs contribute to disease pathogenesis, highlighting both shared and disorder-specific features. Finally, we discuss current therapeutic strategies aimed at modulating the mTOR/4E-BP axis, outline the limitations of existing approaches and identify emerging avenues for drug development. Together, these perspectives underscore the potential of 4E-BPs as both therapeutic targets and biomarkers in neurological disease.

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