eIF2alpha Phosphorylation in Synaptic Plasticity, Memory, and Brain Disorders

描述（由申请人提供）：关于阿尔茨海默病（AD）中改变的分子信号传导途径，以及这些途径的失调是否有助于与AD相关的突触可塑性和记忆缺陷的损伤，普遍缺乏了解。eIF 2有四种已知的蛋白激酶：一般控制非去阻遏蛋白激酶2（GCN 2），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）驻留蛋白激酶（PERK）。eIF 2的磷酸化在丝氨酸51上的突变导致一般翻译起始的减少，但它也选择性地增加在其5'非翻译区（UTR）中含有上游开放阅读框（uORF）的mRNA子集的翻译。先前的研究表明，在AD模型小鼠的大脑和AD患者的死后大脑中，eIF 2 <$磷酸化增加，这表明增加的eIF 2 <$磷酸化减少了一般翻译，并上调了AD中UTR中具有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的基因缺失可以防止AD模型小鼠中一般翻译的减少、ATF 4（其mRNA含有uORF）表达的增加、突触可塑性的损伤和记忆缺陷。基于这些观察结果，我们提出了一个中心假设，即AD中eIF 2磷酸化水平升高通过激活多种eIF 2激酶导致突触可塑性受损和记忆缺陷，这是由于mRNA翻译和蛋白表达差异所致。为了验证这一假设，我们将1）确定GCN 2和PKR的基因缺失是否阻止AD模型小鼠中改变的翻译控制和淀粉样蛋白生成，2）确定GCN 2和PKR的基因缺失是否阻止AD模型小鼠显示的突触可塑性和记忆缺陷中的衰老相关损伤，3）确定AD模型小鼠和eIF 2中合成和表达改变的蛋白质的身份。激酶突变小鼠。这些研究将提供重要的信息，关于通过GCN 2和/或PKR的缺失减少eIF 2 <$磷酸化是否可以以类似于PERK缺失的方式纠正AD模型小鼠中失调的翻译、受损的突触可塑性和记忆缺陷，以及这些eIF 2 <$激酶是否可能是AD的合适治疗靶点。此外，这些研究有可能通过鉴定AD小鼠大脑中翻译失调的蛋白质以及其翻译受每个eIF 2？激酶调节的蛋白质来鉴定其他靶点。

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.