Translational control in aging and neurodegeneration

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

Decoupling of mRNA and protein expression in aging brains reveals the age-dependent adaptation of specific gene subsets

“…During aging, the global translation rate decreases as the translation machinery becomes less efficient. This decrease is due to the deregulation of the stoichiometry of translation components that affects the abundance of ribosomes (Dhondt et al 2017; Janssens et al 2015) but also the rate and accuracy of translation (Gonskikh and Polacek 2017; Skariah and Todd 2021). Therefore, the age-dependent enrichment of ribosome components might affect protein homeostasis and promote a loss of proteostasis, one of the primary hallmarks of aging.…”

Functions and Regulation of Translation Elongation Factors

“…Single-cell transcriptomic analysis revealed that the expression level of eEF1A1 in neurons was low and changed with age in glial cells ( Ximerakis et al, 2019 ). Therefore, eEF1A may represent a potential candidate for lifespan modulation ( Skariah and Todd, 2020 ). In addition, eEF1A, along with eEF2, has been shown to be related to neurodegenerative disorders including Alzheimer disease (AD) and Parkinson disease (PD) with an unknown mechanism.…”

“…In addition, eEF1A, along with eEF2, has been shown to be related to neurodegenerative disorders including Alzheimer disease (AD) and Parkinson disease (PD) with an unknown mechanism. The low expression levels of these factors in the brains of AD and PD patients indicating defects in the efficiency or fidelity of translation ( Li et al, 2005 ; Vera et al, 2014 ; Garcia-Esparcia et al, 2015 ; Beckelman et al, 2016 ; Skariah and Todd, 2020 ). eEF1A has chaperone-like activity ( Lukash et al, 2004 ) and may also be involved in antiviral response by interaction with Sgt1, a multifunctional protein ( Novosylna et al, 2015 ).…”

Repeat RNA Toxicity Drives Ribosomal RNA Processing Defects in SCA2

“…Within the context of an aging neuronal environment, the accumulation of expanded repeat containing RNA and proteins could trigger cascades of events that affect both arms of the peptide life cycle—synthesis and degradation—precipitating neurodegeneration 32 …”