eIF2alpha Phosphorylation in Synaptic Plasticity, Memory, and Brain Disorders

eIF2alpha 磷酸化在突触可塑性、记忆力和大脑疾病中的作用

基本信息

批准号：
8821675
负责人：
Eric Klann
金额：
$ 46.28万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-05-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8821675
关键词：
5&apos Untranslated Regions APP-PS1 Accounting Address Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acids Autopsy Behavioral Brain Brain Diseases CREB1 gene Cell Culture Techniques Cells Coupled Data Disease Disease model Double-Stranded RNA Endoplasmic Reticulum Functional disorder Funding Gene Expression Genes Genetic Genetic Translation Health Heme Homeostasis Impairment Light Long-Term Potentiation Measures Memory Memory Loss Memory impairment Messenger RNA Molecular Mus Mutant Strains Mice Nerve Degeneration Neurodegenerative Disorders Open Reading Frames Pathway interactions Patients Peptide Initiation Factors Phosphorylation Phosphotransferases Physiological Prion Diseases Prosencephalon Protein Biosynthesis Protein Kinase Proteins Reporting Resources Role Serine Signal Pathway Stable Isotope Labeling Stress Surface Synapses Synaptic plasticity Techniques Testing Time Translation Initiation Translations Untranslated Regions Up-Regulation age related amyloidogenesis base brain tissue combinatorial eIF-2 Kinase inhibitor/antagonist innovation insight long term memory memory consolidation neuron loss new therapeutic target novel therapeutics prevent protein expression research study response restoration spatial memory stressor synaptic failure therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：对于阿尔茨海默病（AD）中改变的分子信号传导途径以及这些途径的失调是否会导致与 AD 相关的突触可塑性损伤和记忆缺陷，人们普遍缺乏了解。在这一竞争性更新中，重点关注翻译起始因子 eIF2 的磷酸化。以及磷酸化 eIF2 的蛋白激酶。具有四种已知的蛋白激酶：通用控制非去阻遏蛋白激酶 2 (GCN2)、双链 RNA 激活蛋白激酶 (PKR)、血红素调节抑制剂 (HRI) 和 PKR 样内质网 (ER) 驻留蛋白eIF2 的磷酸化。丝氨酸 51 上的修饰会导致一般翻译起始的减少，但它也会选择性地增加 5' 非翻译区 (UTR) 中包含上游开放阅读框 (uORF) 的 mRNA 子集的翻译。 AD 模型小鼠的大脑和 AD 患者死后大脑中的磷酸化增加，表明 eIF2 增加在 AD 中，磷酸化会降低一般翻译并上调其 UTR 中带有 uORF 的 mRNA 的翻译，与这一观点一致，在之前的资助期间，我们发现 PERK 的基因删除可防止一般翻译的减少和 ATF4 表达的增加（其 mRNA 包含 a）。 uORF）、AD模型小鼠的突触可塑性受损和记忆缺陷基于这些观察，我们制定了一个中心假设，即 eIF2 升高。 AD 中通过激活多个 eIF2 进行磷酸化？由于 mRNA 翻译和蛋白质表达差异，激酶导致突触可塑性受损和记忆缺陷。为了检验这一假设，我们将 1) 确定 GCN2 和 PKR 的基因缺失是否会阻止 AD 模型小鼠的翻译控制和淀粉样蛋白生成的改变，2) 确定是否。 GCN2 和 PKR 的基因删除可防止 AD 模型小鼠表现出的与衰老相关的突触可塑性损伤和记忆缺陷，以及 3) 确定 AD 模型小鼠中合成和表达改变的蛋白质的身份在 eIF2 中??这些研究将提供有关 eIF2 是否减少的重要信息。通过删除 GCN2 和/或 PKR 进行磷酸化可以以类似于删除 PERK 的方式纠正 AD 模型小鼠中翻译失调、突触可塑性受损和记忆缺陷，以及这些 eIF2 是否此外，这些研究有可能通过识别 AD 小鼠大脑中翻译失调的蛋白质以及翻译受每个 eIF2 调节的蛋白质来确定其他靶点。激酶。