Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer’s disease

Page, Guylène; Bilan, Agnès Rioux; Ingrand, Sabrina; Lafay-Chebassier, Claire; Pain, Stéphanie; Pochat, M.C. Perault; Bouras, Constantin; Bayer, Thomas A.; Hugon, Jacques

doi:10.1016/j.neuroscience.2006.01.047

Cited by 96 publications

(89 citation statements)

References 43 publications

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“…Here, we showed an intense nuclear translocation of pT 451 -PKR in A␤42-treated SH-SY5Y cells as described in APP SL PS1 KI mouse brains and in AD patients (6,9), which was associated with a clear nuclear translocation of pS 194 -FADD. PKR contains nuclear localization signals (NLS), (36,37).…”

Section: Discussionsupporting

confidence: 78%

“…FasL Levels and Physical Interaction between PKR and FADD in APP SL PS1 KI Mice-These mice displayed a massive neuronal loss as early as 6 months of age with an intense neuronal apoptosis (9,21). This neuronal loss distribution closely parallels the strong intraneuronal A␤ immunostaining and intracellular thioflavin-S-positive material but does not correlate with extracellular deposits (26).…”

Section: Physical Interaction Between Pkr and Fadd In A␤42-treated Shmentioning

confidence: 93%

“…Our previous studies reported under the same experimental conditions that 2 M (10-fold of IC 50 ) C16 clearly inhibited the pT 451 -PKR levels in A␤42-treated SH-SY5Y cells (9). pT 451 -PKR and pS 194 -FADD were analyzed in nuclear extracts of SH-SY5Y cells pretreated with 2 M C16 1 h before 20-M A␤42 treatment for 4 h by immunoblot.…”

Section: Physical Interaction Between Pkr and Fadd In A␤42-treated Shmentioning

confidence: 93%

“…All animal experiments were performed in compliance and following approval of the Sanofi-Aventis Animal Care and Use Committee in accordance with standards of the guide for the care and use of laboratory animals (CNRS ILAR) and with respect to French and European Community rules. Brain tissue preparation was performed as previously described (9).…”

Section: Methodsmentioning

confidence: 99%

“…They revealed that activated double-stranded RNA-dependent protein kinase (PKR), which phosphorylates the ␣-subunit of eIF2, was associated with degenerating neurons in AD brains (6 -8). Furthermore, the levels of phosphorylated forms of PKR and eIF2␣ were significantly increased in AD cellular models exposed to A␤42 (2,5) in the brain of AD transgenic mice (1,9) and in lymphocytes of AD patients (10). These modifications were negatively correlated with cognitive and memory test scores performed in AD patients (3,10,11).…”

mentioning

confidence: 96%

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Interaction of Double-stranded RNA-dependent Protein Kinase (PKR) with the Death Receptor Signaling Pathway in Amyloid β (Aβ)-treated Cells and in APPSLPS1 Knock-in Mice

Couturier

Morel

Pontcharraud

et al. 2010

Journal of Biological Chemistry

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Alzheimer Disease (AD)2 is the leading cause of dementia in the elderly, affecting 25 million people in the world with about 5% of genetic origin. The biological features of AD are neuronal loss, senile plaques predominantly composed of amyloid ␤ peptide (A␤), and the presence of neurofibrillary tangles, leading to a progressive deterioration of cognitive function with loss of memory. Unfortunately, no definitive therapy for AD exists.The involvement of A␤ is clearly established, but mechanisms that underlie neuronal death are currently under investigation. For 10 years, research has focused on pathways controlling translation (1-5). They revealed that activated double-stranded RNA-dependent protein kinase (PKR), which phosphorylates the ␣-subunit of eIF2, was associated with degenerating neurons in AD brains (6 -8). Furthermore, the levels of phosphorylated forms of PKR and eIF2␣ were significantly increased in AD cellular models exposed to A␤42 (2, 5) in the brain of AD transgenic mice (1, 9) and in lymphocytes of AD patients (10). These modifications were negatively correlated with cognitive and memory test scores performed in AD patients (3, 10, 11). Besides its important role as a translational regulator, PKR is a key mediator in different signaling pathways. Indeed, among its downstream targets, the Fas-associated protein with a death domain (FADD) and subsequent caspase-8 are responsible for PKR-induced apoptosis in virus-infected cells (12). Furthermore, the overexpression of a dominant-negative FADD construct rescued SH-SY5Y cells from either tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or A␤-induced neurotoxicity (13). FADD could be involved in apoptosis through its nuclear localization by interacting with the methylCpG binding domain protein 4 (MDB4), a protein known to be implicated in DNA repair, but that could promote apoptosis when associated with FADD (14). Furthermore, many postmortem studies have reported the role of the FADD-linked death receptor signaling pathway in the pathobiology of AD (15-17).However, control of FADD under the PKR activation in AD remains unknown. The present study performed a detailed analysis of PKR and FADD interaction in A␤-treated cells and in APP SL PS1 KI transgenic mice. The purpose is to determine if inhibition of PKR could reduce apoptosis through the decrease in this death adaptor activation. Here, we showed a physical interaction between PKR and FADD in nuclei of A␤42-treated SH-SY5Y and in APP SL PS1 KI mice. Furthermore, PKR inhibitory treatments prevented not only the nuclear translocation of FADD but also significantly decreased caspase-3 and -8 activities induced by A␤ neurotoxicity. EXPERIMENTAL PROCEDURES

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Section: Discussionsupporting

confidence: 78%

Section: Physical Interaction Between Pkr and Fadd In A␤42-treated Shmentioning

confidence: 93%

Section: Physical Interaction Between Pkr and Fadd In A␤42-treated Shmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 96%

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Interaction of Double-stranded RNA-dependent Protein Kinase (PKR) with the Death Receptor Signaling Pathway in Amyloid β (Aβ)-treated Cells and in APPSLPS1 Knock-in Mice

Couturier

Morel

Pontcharraud

et al. 2010

Journal of Biological Chemistry

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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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Lithium chloride and staurosporine potentiate the accumulation of phosphorylated glycogen synthase kinase 3β/Tyr216, resulting in glycogen synthase kinase 3β activation in SH‐SY5Y human neuroblastoma cell lines

Noël

Barrier

Rinaldi

et al. 2011

J of Neuroscience Research

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Glycogen synthase kinase 3β (GSK3β) activity is regulated by phosphorylation processes and regulates in turn through phosphorylation several proteins, including eukaryotic initiation factor 2B (eIF2B). Serine 9 phosphorylation of GSK3β (pGSK3βSer9), usually promoted by activation of the PI3K/Akt survival pathway, triggers GSK3β inhibition. By contrast, tyrosine 216 phosphorylation of GSK3β (pGSK3βTyr216) increases under apoptotic conditions, leading to GSK3β activation. Lithium chloride (LiCl) is usually described to increase pGSK3βSer9 through the PI3K/Akt pathway, resulting in GSK3β inhibition. The purpose of this study is to demonstrate that in some cases LiCl is also able to increase pGSK3βTyr216, resulting in GSK3β activation. For this, we used SH-SY5Y cells and primary neuronal cultures and investigated the effects of LiCl on the two phosphorylated forms of GSK3β under staurosporine (STS)-intoxicated conditions. The ratios between the phosphorylated and total forms of GSK3β and eIF2B were determined by Western blotting. Our results revealed that, besides its ability to increase pGSK3βSer9, LiCl is also able to increase pGSK3βTyr216 greatly in STS-intoxicated SH-SY5Y cells but not in STS-intoxicated primary neuronal cultures. This accumulation of both Ser9 and Tyr216 phosphorylation results in GSK3β activation in STS-intoxicated SH-SY5Y cells in spite of the presence of LiCl. These findings indicate that LiCl treatment is not necessarily correlated with GSK3β inhibition even though it generates Ser9 phosphorylation. Consequently, the ratio pGSK3βSer9/pGSK3βTyr216, which takes into account the balance between the two inactive (Ser9) and active (Tyr216) forms of GSK3β, could be more useful for predicting GSK3β inhibition.

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Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer’s disease

Cited by 96 publications

References 43 publications

Interaction of Double-stranded RNA-dependent Protein Kinase (PKR) with the Death Receptor Signaling Pathway in Amyloid β (Aβ)-treated Cells and in APPSLPS1 Knock-in Mice

Interaction of Double-stranded RNA-dependent Protein Kinase (PKR) with the Death Receptor Signaling Pathway in Amyloid β (Aβ)-treated Cells and in APPSLPS1 Knock-in Mice

Translational control by eIF2α in neurons: Beyond the stress response

Lithium chloride and staurosporine potentiate the accumulation of phosphorylated glycogen synthase kinase 3β/Tyr216, resulting in glycogen synthase kinase 3β activation in SH‐SY5Y human neuroblastoma cell lines

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