Neuronal Regulation of eIF2α Function in Health and Neurological Disorders

A key site of translation control is the phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α), which reduces the rate of GDP to GTP exchange by eIF2B, leading to altered translation. The extent of eIF2α phosphorylation within neurons can alter synaptic plasticity. Phosphorylation of eIF2α is triggered by four stress-responsive kinases, and as such eIF2α is often phosphorylated during neurological perturbations or disease. Moreover, in some cases decreasing eIF2α phosphorylation mitigates neurodegeneration, suggesting that this could be a therapeutic target. Mutations in the γ subunit of eIF2, the guanine exchange factor eIF2B, an eIF2α phosphatase, or in two eIF2α kinases can cause disease in humans, demonstrating the importance of proper regulation of eIF2α phosphorylation for health.