PKR Inhibition Rescues Memory Deficit and ATF4 Overexpression in ApoE ε4 Human Replacement Mice

Segev, Yifat; Barrera, Iliana; Ounallah-Saad, Hadile; Wibrand, Karin; Sporild, Ida; Livne, Adva; Rosenberg, Tali; David, Orit; Mints, Meshi; Bramham, Clive R.; Rosenblum, Kobi

doi:10.1523/jneurosci.5241-14.2015

Cited by 54 publications

(52 citation statements)

References 54 publications

(3 reference statements)

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“…Nevertheless, increasing translation could ameliorate the disease. Indeed, both genetic reduction of eIF2α phosphorylation (PKR or PERK knockout mice and GADD34-overexpressing vectors) or pharmacological correction of the abnormal translational program controlled by eIF2α (e.g., using ISRIB and PKR inhibitors) reverses the cognitive decline associated with AD (Lourenco et al 2013;Ma et al 2013;Segev et al 2015), traumatic brain injury (Chou et al 2017), as well as the pathology associated with prion disease (Moreno et al 2012).…”

Section: Perturbed Translational Control In Neurological Disordersmentioning

confidence: 99%

Translational Control in the Brain in Health and Disease

Sossin

Costa-Mattioli

2018

Cold Spring Harb Perspect Biol

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Translational control in neurons is crucially required for long-lasting changes in synaptic function and memory storage. The importance of protein synthesis control to brain processes is underscored by the large number of neurological disorders in which translation rates are perturbed, such as autism and neurodegenerative disorders. Here we review the general principles of neuronal translation, focusing on the particular relevance of several key regulators of nervous system translation, including eukaryotic initiation factor 2α (eIF2α), the mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1), and the eukaryotic elongation factor 2 (eEF2). These pathways regulate the overall rate of protein synthesis in neurons and have selective effects on the translation of specific messenger RNAs (mRNAs). The importance of these general and specific translational control mechanisms is considered in the normal functioning of the nervous system, particularly during synaptic plasticity underlying memory, and in the context of neurological disorders.

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Section: Perturbed Translational Control In Neurological Disordersmentioning

confidence: 99%

Translational Control in the Brain in Health and Disease

Sossin

Costa-Mattioli

2018

Cold Spring Harb Perspect Biol

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“…Interestingly, ATF4 seems to be locally translated in axons in response to Aβ peptide stimulation and in addition it is retrogradely transported, which is necessary for Aβ‐mediated cell death [Baleriola et al, ]. Genetic and environmental risk factors for sporadic AD are also associated with increased eIF2α phosphorylation in mouse models [Segev et al, ]. Interestingly, eIF2α phosphorylation increases the translation of BACE1, one of the enzymes responsible for APP cleavage, suggesting a vicious cycle, in which phosphorylated eIF2α promotes Aβ production and vice‐versa [O'Connor et al, ; Mouton‐Liger et al, ; Devi and Ohno, ].…”

Section: Eif2α In Neurodegenerative Diseasesmentioning

confidence: 99%

Translational control by eIF2α in neurons: Beyond the stress response

Bellato

Hajj

2016

Cytoskeleton

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The translation of mRNAs is a tightly controlled process that responds to multiple signaling pathways. In neurons, this control is also exerted locally due to the differential necessity of proteins in axons and dendrites. The phosphorylation of the alpha subunit of the translation initiation factor 2 (eIF2a) is one of the mechanisms of translational control. The phosphorylation of eIF2a has classically been viewed as a stress response, halting translation initiation. However, in the nervous system this type of regulation has been related to other mechanisms besides stress response, such as behavior, memory consolidation and nervous system development. Additionally, neurodegenerative diseases have a major stress component, thus eIF2a phosphorylation plays a preeminent role and its modulation is currently viewed as a new opportunity for therapeutic interventions. This review consolidates current information regarding eIF2a phosphorylation in neurons and its impact in neurodegenerative diseases. V C 2016 Wiley Periodicals, Inc.Key Words: neuron; mRNA translation; eIF2a; neurodegenerative diseases; memory consolidation Introduction T he precise control of protein synthesis is essential to all physiological processes and, in neurons, this necessity is taken to an extreme, due to local specialized needs of neuronal processes such as axons and dendrites. One of the mechanisms that control translation is the phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF2a). Classically viewed as a stress response, this pathway was surprisingly implicated in normal neuronal processes, such as memory consolidation. This review will summarize the mechanisms of eIF2a in translational control and how this affects neuronal physiological and pathological processes. Translation Initiation and Polysome FormationTranslation of mRNAs is divided into three different steps: initiation, elongation and termination. Initiation is the most tightly regulated phase, with diverse mechanisms dedicated to induce and abolish the translation of mRNAs [Mathews et al., 2007].Translation initiation starts by the binding of translation initiation factors (here we will only refer to the translation of eukaryotes and their respective initiation factors, or eukaryotic initiation factors [eIFs]) to the modified structures of the mRNAs (the 5 0 terminal m7G cap and the 3 0 Poly(A) tail) [Pestova et al., 2007]. The initiation factor eIF4F (a complex formed by the proteins eIF4E, eIF4G and eIF4A) binds to the 5 0 Cap and the polyadenylate-binding protein (PABP) interacts with the Poly(A) tail. PABP and eIF4F interact with each other in a configuration that circularizes the mRNA. Interestingly, the circularization facilitates translation by recycling terminating ribosomes, ensuring that only intact mRNAs are translated and protecting mRNA from degradation [Jackson et al., 2010].Once mRNA is circularized, it has to assemble an elongation-competent 80S ribosome from the 40S and 60S ribosomal subunits, which is achieved in a multi-step manne...

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“…At the same time, dysregulation of these mechanisms underlies various neurodevelopmental and neurodegenerative pathologies. Both the initiation and elongation phases of mRNA translation and the respective translation factors that mediate them have been suggested as innovative targets for memory enhancement in health and disease (56,(59)(60)(61)(62)(63)111).…”

Section: Introductionmentioning

confidence: 99%

Measuring mRNA translation in neuronal processes and somata by tRNA-FRET

Koltun

Ironi

Gershoni-Emek

et al. 2019

Preprint

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In neurons, the specific spatial and temporal localization of protein synthesis is of great importance for function and survival. In this work, we visualized tRNA and protein synthesis events in fixed and live mouse primary cortical culture using fluorescently-labeled tRNAs. We were able to characterize the distribution and movement of tRNAs in different neuronal sub-compartments and to study their association with the ribosome. We found that tRNA motion in neural processes is lower than in somata and corresponds to patterns of slow transport mechanisms, and that larger tRNA puncta co-localize with translational machinery components and are likely the functional fraction. Furthermore, chemical induction of LTP in culture revealed GluR-dependent biphasic up-regulation of mRNA translation with a similar effect in dendrites and somata. Importantly, measurement of protein synthesis in neurons with high resolutions offers new insights into neuronal function in health and disease states.

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PKR Inhibition Rescues Memory Deficit and ATF4 Overexpression in ApoE ε4 Human Replacement Mice

Cited by 54 publications

References 54 publications

Translational Control in the Brain in Health and Disease

Translational Control in the Brain in Health and Disease

Translational control by eIF2α in neurons: Beyond the stress response

Measuring mRNA translation in neuronal processes and somata by tRNA-FRET

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