Axonally Synthesized ATF4 Transmits a Neurodegenerative Signal across Brain Regions

Baleriola, Jimena; Walker, Chandler A.; Jean, Ying Y.; Crary, John F.; Troy, Carol M.; Nagy, Péter L.; Hengst, Ulrich

doi:10.1016/j.cell.2014.07.001

Cited by 292 publications

(285 citation statements)

References 61 publications

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“…Our findings support a model in which the retrograde transport of locally synthesized ATF4 causes transcriptional changes in the neuronal cell bodies that eventually lead to neurodegeneration and loss of neurons. In fact, we found increased ATF4 transcript and protein within axons in the brain of patients with AD [45], further supporting this model of long-range transmission of a neurodegenerative signal via locally synthesized ATF4. Together, our results establish that intra-axonal protein synthesis is functionally significant in a neurodegenerative disorder and indicatea potential therapeutic strategy to slow down or interrupt the long-range transmission of neurodegeneration across the brain in AD.…”

Section: Neurodegenerative Disorderssupporting

confidence: 84%

“…Importantly, ATF4 is not the only axonally recruited mRNA found in axons upon treatment with Aβ [45]. When clustered in gene ontology term categories, the mRNAs found in vehicle and Aβ 1-42 -treated axons overlap in many gene ontology terms, but 33 are unique to control axons and 54 to Aβ 1-42 -treated axons.…”

Section: Neurodegenerative Disordersmentioning

confidence: 97%

“…Recently, our laboratory uncovered a crucial role of intraaxonal protein synthesis in the pathogenesis of Alzheimer's disease (AD) [45]. AD is the leading cause for age-related dementia and, in the context of an aging society, a pressing public health challenge.…”

Section: Neurodegenerative Disordersmentioning

confidence: 99%

“…For example, the exposure of isolated axons to soluble oligomeric Aβ might be sufficient to change the composition of the axonally localized transcriptome and to activate intra-axonal protein synthesis in a manner analogous to the changes observed in mature axons after injury. Indeed, specific axonal application Aβ 1-42 changed the composition of the axonal transcriptome through recruitment of a defined set of mRNAs, including the transcript coding for the transcription factor activating transcription factor 4 (ATF4) [45]. Treatment of axons with Aβ 1-42 triggered local synthesis of ATF4.…”

Section: Neurodegenerative Disordersmentioning

confidence: 99%

“…Embryonic hippocampal neurons were cultured in compartmentalized chambers for 9-10 days, the axons only were specifically treated with Aβ 1-42 for 24 h, and the composition of the axonal transcriptomes were determined by RNAsequencing [45].…”

Section: Neurodegenerative Disordersmentioning

confidence: 99%

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Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Baleriola

Hengst

2015

Neurotherapeutics

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Localized protein synthesis is a mechanism by which morphologically polarized cells react in a spatially confined and temporally acute manner to changes in their environment. During the development of the nervous system intra-axonal protein synthesis is crucial for the establishment of neuronal connections. In contrast, mature axons have long been considered as translationally inactive but upon nerve injury or under neurodegenerative conditions specific subsets of mRNAs are recruited into axons and locally translated. Intra-axonally synthesized proteins can have pathogenic or restorative and regenerative functions, and thus targeting the axonal translatome might have therapeutic value, for example in the treatment of spinal cord injury or Alzheimer's disease. In the case of Alzheimer's disease the local synthesis of the stress response transcription factor activating transcription factor 4 mediates the long-range retrograde spread of pathology across the brain, and inhibition of local Atf4 translation downstream of the integrated stress response might interfere with this spread. Several molecular tools and approaches have been developed to target specifically the axonal translatome by either overexposing proteins locally in axons or, conversely, knocking down selectively axonally localized mRNAs. Many questions about axonal translation remain to be answered, especially with regard to the mechanisms establishing specificity but, nevertheless, targeting the axonal translatome is a promising novel avenue to pursue in the development for future therapies for various neurological conditions.

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Section: Neurodegenerative Disorderssupporting

confidence: 84%

Section: Neurodegenerative Disordersmentioning

confidence: 97%

Section: Neurodegenerative Disordersmentioning

confidence: 99%

Section: Neurodegenerative Disordersmentioning

confidence: 99%

Section: Neurodegenerative Disordersmentioning

confidence: 99%

See 3 more Smart Citations

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Baleriola

Hengst

2015

Neurotherapeutics

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Spatially and temporally regulating translation via mRNA‐binding proteins in cellular and neuronal function

2017

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Edited by Wilhelm JustCoordinated regulation of mRNA localization and local translation are essential steps in cellular asymmetry and function. It is increasingly evident that mRNA-binding proteins play critical functions in controlling the fate of mRNA, including when and where translation occurs. In this review, we discuss the robust and complex roles that mRNA-binding proteins play in the regulation of local translation that impact cellular function in vertebrates. First, we discuss the role of local translation in cellular polarity and possible links to vertebrate development and patterning. Next, we discuss the expanding role for local protein synthesis in neuronal development and function, with special focus on how a number of neurological diseases have given us insight into the importance of translational regulation. Finally, we discuss the everincreasing set of tools to study regulated translation and how these tools will be vital in pushing forward and addressing the outstanding questions in the field.

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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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Axonally Synthesized ATF4 Transmits a Neurodegenerative Signal across Brain Regions

Cited by 292 publications

References 61 publications

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Spatially and temporally regulating translation via mRNA‐binding proteins in cellular and neuronal function

Translational control by eIF2α in neurons: Beyond the stress response

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