Elucidating the role of the eIF2alpha kinase PERK in synaptic plasticity and memo

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DESCRIPTION (provided by applicant): The overall goal of our lab is to understand the complex molecular mechanisms underlying synaptic plasticity and vertebrate memory formation. My goal is to determine the specific role that the RNA-dependent protein kinase-like endoplasmic reticulum (ER) elF2a kinase (PERK) plays in regulating translation during these processes. PERK primarily has been studied in pancreatic cellular stress response and global brain ischemia; however, its role in protein synthesis-dependent hippocampal synaptic plasticity is poorly understood. In the hippocampus, the generation of new proteins has been shown to be regulated during plasticity via factors involved in the initiation of mRNA translation. A key regulatory step in the initiation of translation is the formation of the preinitiation ternary complex elF2-GTP-Met-tRNAiMet, which is required to bind to the 40S ribosome prior to recognition of mRNA. Upon each round of translation initiation, the guanine-nucleotide exchange factor, elF2B, is required to recycle elF2-GDP to elF2-GTP to regenerate the ternary complex. It has been shown that phosphorylation of the a subunit of elF2 inhibits elF2B activity and eventually decreases translation. Under specific cellular stress conditions, such as an accumulation of unfolded proteins in the ER, PERK phosphorylates elF2a and functions to downregulate general protein synthesis. Understanding the molecular mechanism underlying synaptic plasticity and memory formation is critical to understanding how errors in these processes can lead to cognitive disorders. To this end, I propose experimental research aimed at examining the role of PERK in hippocampus-dependent behavior, synaptic plasticity and the regulation of signal transduction pathways critical to hippocampal long-term potentiation (LTP), long-term depression (LTD) and memory. Specifically, I aim to address the following hypothesis: 1) mGluR-induced PKC signaling modulates PERK-directed elF2a phosphorylation and PERK- dependent translation; 2) PERK is required for the expression of normal hippocampal mGluR-LTD; and 3) PERK is required for hippocampus-dependent forms of learning and memory. Altered protein synthesis has been shown to accompany several human neurological disorders and neurodegenerative diseases including Fragile X linked mental retardation, Alzheimer's disease (AD), Parkinson's disease (PD) and tuberous sclerosis. Thus, abnormal PERK function could be a significant factor underlying the manifestation in severe, debilitating neurological conditions, whereas normal PERK function could play a key role in the molecular mechanisms involved in learning and memory.