The Multifaceted Roles of Eukaryotic Elongation Factor 1-Alpha-2 in Neurodevelopmental and Neurodegenerative Disorders.

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Eukaryotic elongation factor 1-alpha-2 (eEF1A2) is a neuron- and muscle-specific translation elongation factor isoform that supports high-demand proteostasis in terminally differentiated cells. Beyond its canonical role in translation elongation, eEF1A2 participates in noncanonical processes linked to actin cytoskeleton regulation, compartmentalized/local translation, and stress-response signaling. A central challenge in the field is that the strength and type of evidence implicating eEF1A2 differ substantially across disease classes. In neurodevelopmental disorders, heterozygous de novo pathogenic variants in EEF1A2 provide strong causal human genetic evidence for developmental and epileptic encephalopathies and related phenotypes, supported by functional studies showing reduced de novo protein synthesis/elongation and altered actin bundling in common patient-associated variants. In contrast, in neurodegenerative paradigms (e.g., toxin-based Parkinson's disease models and ischemia-reperfusion injury), eEF1A2 is primarily implicated as a contributory node within oxidative stress, autophagy/mitophagy, and inflammatory signaling pathways, largely based on cellular and animal model evidence rather than Mendelian causality. This review adopts an evidence-based framework and organizes findings around a unified mechanistic model connecting canonical elongation and noncanonical cytoskeleton/stress/autophagy functions to neuronal phenotypes. Collectively, current evidence supports a causal role for eEF1A2 in neurodevelopmental disorders but only a contributory role in neurodegenerative conditions.

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