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Translational control in aging and neurodegeneration

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Abstract Protein metabolism plays central roles in age‐related decline and neurodegeneration. While a large body of research has explored age‐related changes in protein degradation, alterations in the efficiency and fidelity of protein synthesis with aging are less well understood. Age‐associated changes occur in both the protein synthetic machinery (ribosomal proteins and rRNA) and within regulatory factors controlling translation. At the same time, many of the interventions that prolong lifespan do so in part by pre‐emptively decreasing protein synthesis rates to allow better harmonization to age‐related declines in protein catabolism. Here we review the roles of translation regulation in aging, with a specific focus on factors implicated in age‐related neurodegeneration. We discuss how emerging technologies such as ribosome profiling and superior mass spectrometric approaches are illuminating age‐dependent mRNA‐specific changes in translation rates across tissues to reveal a critical interplay between catabolic and anabolic pathways that likely contribute to functional decline. These new findings point to nodes in posttranscriptional gene regulation that both contribute to aging and offer targets for therapy. This article is categorized under: Translation > Translation Regulation Translation > Ribosome Biogenesis Translation > Translation Mechanisms
Schematic showing the different stages of protein synthesis. The initiation and elongation factors that are implicated in aging studies are underlined in red. The circled alphabets denote the steps described in the text
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Alterations in translational dynamics with aging. In the healthy brain (top), protein metabolism is maintained in homeostatic balance by the availability of optimal numbers of properly assembled ribosomes (healthy nucleoli), sufficient initiation factors, elongation factors, accurately charged tRNAs (properly functioning tRNA synthetases) and healthy mitochondria that provide sufficient energy for protein synthesis. At the same time, there is precise assembly of proteasomal subunits in the correct stoichiometric ratios along with adequate amounts of chaperones, which are dependent on the protein synthetic machinery for appropriate function and which directly aid in both maintaining translational fidelity and clearance of mistranslated and misfolded proteins (see legend at the bottom for illustrations). Alterations in the stoichiometry of key components of the translation machinery and decreases in the both fidelity of translation and in the corrective measures in place to address mistranslation events emerge with normal aging and are enhanced in pathological age‐associated neurodegenerative conditions. These failures in translation place enhanced burdens upon proteostatic systems both directly (through generation of misfolded proteins) and indirectly (through decrements in generation of functional protein degradation factors). The combinatorial impact of these changes lead to dysregulation in neuronal proteostasis, which feed into one another and contribute to unhealthy cellular environments prone to pathogenic cascades
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Stress, nutrient, and growth factor signaling pathways that affect translation. A large set of signaling cascades link translation dynamics to pathways implicated in both normal and pathological aging. Activation of mTOR by nutrient signaling causes phosphorylation and inactivation of 4EBP and eEF2K, releasing eIF4E and eEF2 respectively to activate translation. Both eIF4E and 4G are targets of Mnk1, which is controlled by p38 MAPK and ERK1/2. ERK1 and 2 respond to IGF/Insulin signaling to activate S6K, which acts on rpS6 and eIF4B to activate translation. Signaling through this pathway also activates PI3K that can directly or indirectly activate AKT. mTOR is acted on by AKT either directly (bold arrow) or indirectly (dotted arrow) via TSC2 (not shown) to inhibit eIF2B. Genotoxic stress activates sestrins (encoded by SESN) to block mTOR signaling and translation through a pathway that involves p53, AMPK and TSC2 (not shown). ER stress activates PERK to phosphorylate and inhibit eIF2. The mTOR pathway also activates ribosome biogenesis. Arrows indicate activation; bar lines indicate suppression. The molecules highlighted in green are targets and pathways for aging interventions (Longo et al., 2015). (For the purposes of clarity, other molecules such as NAD+, sirtuins and epigenetic modulators are not shown.) The downstream translation pathway targets of signaling are highlighted in red. Broken arrows signify additional activators or repressors that are upstream players in that particular cascade. 4EBP, eIF4E binding protein; AKT, serine–threonine kinase AKT; eEF2K, eEF2 kinase; ERK 1/2, extracellular signal‐regulated kinases; GSK3, glycogen synthase kinase 3; Mnk1, mitogen activated protein kinase‐interacting kinase; p38 MAPK, p38 mitogen activating kinase; PERK, pancreatic endoplasmic reticulum eIF2α kinase; PI3K, phosphatidylinositol 3 kinase; rpS6, ribosomal protein S6; S6K, S6 kinase
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Repeat associated non‐AUG (RAN) translation in neurodegeneration. Repeat containing mRNAs form highly stable structures (hairpins or G‐quadruplexes) that cause scanning preinitiation complexes to pause at in‐frame near‐AUG codons or access the RNA through internal ribosomal entry. These processes lead to translation from these repeats in multiple reading frames in the absence of an AUG codon. The repeat mRNA and the resulting protein products elicit cellular stress and activate the ISR pathway, leading to phosphorylation of eIF2α. This in turn selectively activates RAN translation while suppressing global protein synthesis, creating a toxic feed‐forward loop that can lead to neurodegeneration (Cheng et al., 2018; Green et al., 2017; Sonobe et al., 2018; Westergard et al., 2019)
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Translation > Translation Mechanisms
Translation > Ribosome Biogenesis
Translation > Translation Regulation

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