There is a general lack of understanding concerning the molecular signaling pathways that are altered in Alzheimer's disease (AD), and whether dysregulation of these pathways contributes to impairments in synaptic plasticity and memory deficits associated with AD. The studies in this competing renewal are focused on the phosphorylation of the translation initiation factor eIF2 and the protein kinases that phosphorylate it. eIF2 has four known protein kinases: the general control non-derepressible-2 (GCN2), the double-stranded RNA activated protein kinase (PKR), heme-regulated inhibitor (HRI), and the PKR-like endoplasmic reticulum (ER) resident protein kinase (PERK). The phosphorylation of eIF2 on serine 51 causes a decrease in general translation initiation, but it also selectively increases the translation of a subset of mRNAs that contain upstream open reading frames (uORFs) in their 5' untranslated region (UTR). Previous studies showed that eIF2 phosphorylation increased in the brains of AD model mice and postmortem brains from AD patients, suggesting that increased eIF2 phoshorylation decreases general translation and upregulates the translation of mRNAs with uORFs in their UTRs in AD. Consistent with this notion, in the previous funding period we found that genetic deletion of PERK prevents decreases in general translation, increased expression of ATF4 (whose mRNA contains a uORF), impairments in synaptic plasticity, and memory deficits in AD model mice. Based on these observations, we have formulated a central hypothesis, which is that elevated eIF2 phosphorylation in AD via activation of multiple eIF2 kinases results in impaired synaptic plasticity and memory deficits due to differential mRNA translation and protein expression. To test this hypothesis, we will 1) determine whether genetic deletion of GCN2 and PKR prevents altered translational control and amyloidogenesis in AD model mice, 2) determine whether genetic deletion of GCN2 and PKR prevents aging-related impairments in synaptic plasticity and memory deficits displayed by AD model mice, and 3) determine the identity of proteins with altered synthesis and expression in AD model mice and in eIF2 kinase mutant mice. These studies will provide important information concerning whether reduction of eIF2 phosphorylation via deletion of GCN2 and/or PKR can correct dysregulated translation, impaired synaptic plasticity, and memory deficits in AD model mice in a manner similar to the deletion of PERK, and whether these eIF2 kinases might be suitable therapeutic targets for AD. Moreover, these studies have the potential to identify additional targets by identifying the proteins with dysregulated translation in the brains of AD mice, as well as the proteins whose translation is regulated by each eIF2 kinase.
Phosphorylation of the translation initiation factor eIF2? has been shown to regulate protein synthesis during long-lasting synaptic plasticity and long-term memory, and is dysregulated in multiple brain disorders, including Alzheimer's disease (AD). We have proposed experiments to determine whether genetically removing two protein kinases that phosphorylate eIF2? can correct altered protein synthesis, impaired synaptic plasticity, and memory deficits in AD model mice. Thus, our studies have the potential to provide insight into the role of eIF2? phosphorylation in synaptic dysfunction and memory deficits associated with AD, and to identify new therapeutic targets for the treatment of brain disorders associated with dysregulated eIF2? phosphorylation.
|Huynh, T N; Santini, E; Mojica, E et al. (2017) Activation of a novel p70 S6 kinase 1-dependent intracellular cascade in the basolateral nucleus of the amygdala is required for the acquisition of extinction memory. Mol Psychiatry :|
|Ostroff, Linnaea E; Botsford, Benjamin; Gindina, Sofya et al. (2017) Accumulation of Polyribosomes in Dendritic Spine Heads, But Not Bases and Necks, during Memory Consolidation Depends on Cap-Dependent Translation Initiation. J Neurosci 37:1862-1872|
|Yang, Wenzhong; Zhou, Xueyan; Zimmermann, Helena R et al. (2016) Repression of the eIF2? kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer's disease. Neurobiol Aging 41:19-24|
|Bowling, Heather; Bhattacharya, Aditi; Klann, Eric et al. (2016) Deconstructing brain-derived neurotrophic factor actions in adult brain circuits to bridge an existing informational gap in neuro-cell biology. Neural Regen Res 11:363-7|
|Bowling, Heather; Bhattacharya, Aditi; Zhang, Guoan et al. (2016) BONLAC: A combinatorial proteomic technique to measure stimulus-induced translational profiles in brain slices. Neuropharmacology 100:76-89|
|Beckelman, Brenna C; Day, Stephen; Zhou, Xueyan et al. (2016) Dysregulation of Elongation Factor 1A Expression is Correlated with Synaptic Plasticity Impairments in Alzheimer's Disease. J Alzheimers Dis 54:669-78|
|Huynh, Thu N; Shah, Manan; Koo, So Yeon et al. (2015) eIF4E/Fmr1 double mutant mice display cognitive impairment in addition to ASD-like behaviors. Neurobiol Dis 83:67-74|
|Gross, Christina; Chang, Chia-Wei; Kelly, Seth M et al. (2015) Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep 11:727-36|
|Zhang, Guoan; Bowling, Heather; Hom, Nancy et al. (2014) In-depth quantitative proteomic analysis of de novo protein synthesis induced by brain-derived neurotrophic factor. J Proteome Res 13:5707-14|
|Bhattacharya, Aditi; Klann, Eric (2014) (Li+)ghting the way for a treatment for cognitive impairments in fragile X syndrome. Biol Psychiatry 75:175-6|
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