Neuronal Regulation of eIF2 alpha Function in Health and Neurological Disorders

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