Functional Contribution of the Transcription Factor ATF4 to the Pathogenesis of Amyotrophic Lateral Sclerosis

Matus, Soledad; López, Estefanía; Valenzuela, Vicente; Nassif, Melissa; Hetz, Claudio

doi:10.1371/journal.pone.0066672

Cited by 85 publications

(64 citation statements)

References 55 publications

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“…In prion diseases, XBP1 deficiency did not have any effects (53). In contrast, targeting PERK/ATF4 signaling in ALS (106) or prion diseases (112) protects against degeneration; it has no effects in Huntington's disease (157) and exacerbates the effects of spinal cord injury (155). The relevance of the UPR in brain disorders seems to be specific to distinct diseases, therefore, a systematic study of the functional significance of ER stress is needed to understand the contribution of UPR in neurodegeneration.…”

Section: C588mentioning

confidence: 90%

Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 1. An overview

Dufey

Sepúlveda

Rojas‐Rivera

et al. 2014

American Journal of Physiology-Cell Physiology

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156

129

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Increased demand on the protein folding capacity of the endoplasmic reticulum (ER) engages an adaptive reaction known as the unfolded protein response (UPR). The UPR regulates protein translation and the expression of numerous target genes that contribute to restore ER homeostasis or induce apoptosis of irreversibly damaged cells. UPR signaling is highly regulated and dynamic and integrates information about the type, intensity, and duration of the stress stimuli, thereby determining cell fate. Recent advances highlight novel physiological outcomes of the UPR beyond specialized secretory cells, particularly in innate immunity, metabolism, and cell differentiation. Here we discuss studies on the fine-tuning of the UPR and its physiological role in diverse organs and diseases.

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Section: C588mentioning

confidence: 90%

Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 1. An overview

Dufey

Sepúlveda

Rojas‐Rivera

et al. 2014

American Journal of Physiology-Cell Physiology

Self Cite

156

129

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“…CHOP, a transcription factor upregulated in response to ER stress, is also capable of directly transactivating Bim and Puma promoters . Thus, ER stress may trigger Bim and Puma upregulation via cooperation between CHOP and FoxO3a transcription factors in neurons . Interestingly, another cyclin‐dependent kinase, Cdk4, which is able to induce E2F1‐dependent transcriptional upregulation of B‐Myb transcription factor, is also required for Bim upregulation and neuronal death .…”

Section: Cell Death Controls In Neurons: Bcl‐2 Family Proteinsmentioning

confidence: 99%

Apoptotic cell death regulation in neurons

2019

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Apoptosis plays a major role in shaping the developing nervous system during embryogenesis as neuronal precursors differentiate to become post‐mitotic neurons. However, once neurons are incorporated into functional circuits and become mature, they greatly restrict their capacity to die via apoptosis, thus allowing the mature nervous system to persist in a healthy and functional state throughout life. This robust restriction of the apoptotic pathway during neuronal differentiation and maturation is defined by multiple unique mechanisms that function to more precisely control and restrict the intrinsic apoptotic pathway. However, while these mechanisms are necessary for neuronal survival, mature neurons are still capable of activating the apoptotic pathway in certain pathological contexts. In this review, we highlight key mechanisms governing the survival of post‐mitotic neurons, while also detailing the physiological and pathological contexts in which neurons are capable of overcoming this high apoptotic threshold.

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“…On the other hand, studies by different groups have opposite results on the role of eIF2α phosphorylation, suggesting that this overextended stress response is deleterious. Mutant SOD models that are ATF4 knockout, thus reducing the impact of eIF2α phosphorylation, displayed delayed disease onset and prolonged life span [Matus et al, ]. In addition, other studies reporting treatment of mutant SOD mice with Guanabenz accelerated ALS‐like disease progression [Vieira et al, ].…”

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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Functional Contribution of the Transcription Factor ATF4 to the Pathogenesis of Amyotrophic Lateral Sclerosis

Cited by 85 publications

References 55 publications

Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 1. An overview

Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 1. An overview

Apoptotic cell death regulation in neurons

Translational control by eIF2α in neurons: Beyond the stress response

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