Activation of eukaryotic initiation factor-2α-kinases in okadaic acid-treated neurons

• Published in: Neuroscience Vol. 169; no. 4; pp. 1831 - 1839
• Main Authors: Kim, S.M, Yoon, S.Y, Choi, J.E, Park, J.S, Choi, J.M, Nguyen, T, Kim, D.H
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-09-2010; Elsevier
• Subjects: Alzheimer's disease; amino acids-regulated eIF2α kinase; Animals; Biological and medical sciences; Cells, Cultured; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; double-stranded RNA-dependent protein kinase; eIF-2 Kinase - metabolism; Enzyme Activation - drug effects; Enzyme Activation - physiology; Enzyme Inhibitors - pharmacology; Eukaryotic Initiation Factor-2 - metabolism; eukaryotic initiation factor-2α; Fundamental and applied biological sciences. Psychology; Medical sciences; Nerve Degeneration - metabolism; Nerve Degeneration - physiopathology; Neurology; Neurons - drug effects; Neurons - metabolism; Okadaic Acid - pharmacology; PKR-like endoplasmic reticulum kinase; Protein Kinases - metabolism; Rats; Vertebrates: nervous system and sense organs; APP; heme-regulated eIF2α kinase; neurofibrillary tangles; PERK; okadaic acid; amino acids-regulated eIF2α kinase; Aβ; OA; amyloid precursor protein; UPR; eukaryotic initiation factor-2α; protein phosphatase-2A; Alzheimer's disease; NFT; β-amyloid; GCN2; AD; PKR inhibitor; PP2A; ER; PKR-like endoplasmic reticulum kinase; eIF2α; unfolded protein response; PKR; PKRi; double-stranded RNA-dependent protein kinase; endoplasmic reticulum; HRI; ATF4; activating transcription factor 4; Nervous system diseases; Enzyme; Alzheimer disease; Transferases; Non-specific serine/threonine protein kinase; Cerebral disorder; Neuron; Kinase; Aminoacid; Central nervous system disease; Okadaic acid; Degenerative disease; Endoplasmic reticulum
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2010.06.016

Abstract Phosphorylation of eukaryotic initiation factor-2α (eIF2α) is increased in Alzheimer's disease (AD) and this protein can be phosphorylated by several kinases, including double-stranded RNA-dependent protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), amino acids-regulated eIF2α kinase (GCN2) and heme-regulated eIF2α kinase (HRI). PKR and PERK especially are activated in the AD brain, and GCN2 is reported to increase presenilin-1 (PS1) activity. Okadaic acid (OA), a protein phosphatase-2A (PP2A) inhibitor, is known to increase tau phosphorylation, β-amyloid (Aβ) deposition and neuronal death, which are the pathological characteristics of AD. Here, we show that the phosphorylation of eIF2α is increased and its kinases, PKR, PERK and GCN2 are activated in rat neurons by OA. Activating transcription factor (ATF4) which induces apoptosis in response to eIF2α phosphorylation was increased and translocated to nuclei in OA-treated neurons. These results suggest that the successive events of activation of eIF2α kinases and eIF2α phosphorylation leading to ATF4 nuclear translocation may contribute to neuronal death. However, PKR inhibitors did not reduce eIF2α phosphorylation or neuronal toxicity despite inhibiting PKR activity. These results suggest that PKR might not be the most responsible kinase for eIF2α phosphorylation or cell death in PP2A-inhibited conditions such as AD.