Neuronal Regulation of eIF2α Function in Health and Neurological Disorders. Issue 6 (June 2018)

• Record Type: Journal Article
• Authors: Moon, Stephanie L.; Sonenberg, Nahum; Parker, Roy
• Is Part Of: Trends in molecular medicine. Volume 24:Issue 6(2018)
• Page Start: 575
• Page End: 589
• Publication Date: 2018-06
• Subjects: Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; Physiology, Pathological -- Periodicals; 572.8
• DOI: 10.1016/j.molmed.2018.04.001
• Languages: English
• ISSNs: 1471-4914

Abstract

Abstract : 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. Highlights: Phosphorylation of eIF2α is a key regulatory target for translation control that is important in regulating translation during normal and stress conditions. Emerging data highlight that eIF2α phosphorylation is crucial in neuronal function and impacts synaptic plasticity as well as being inappropriately increased in numerous neurodegenerative diseases. Mutations in components of the eIF2α phosphorylation circuit give rise to human diseases, often including neurological and/or neurodegenerative pathologies. In model systems of neurological disease with perturbed eIF2α function, therapeutic restoration of proper eIF2α control can decrease the severity of disease via targeting of eIF2α kinases or phosphatases, or by mitigating phospho-eIF2α activity. The regulation of eIF2α phosphorylation is a promising therapeutic target for the treatment of neurological diseases.