mRNA Translation Gone Awry: Translation Fidelity and Neurological Disease

Abstract

Errors during mRNA translation can lead to a reduction in the levels of functional proteins and an increase in deleterious molecules. Advances in next-generation sequencing have led to the discovery of rare genetic disorders, many caused by mutations in genes encoding the mRNA translation machinery, as well as to a better understanding of translational dynamics through ribosome profiling. We discuss here multiple neurological disorders that are linked to errors in tRNA aminoacylation and ribosome decoding. We draw on studies from genetic models, including yeast and mice, to enhance our understanding of the translational defects observed in these diseases. Finally, we emphasize the importance of tRNA, their associated enzymes, and the inextricable link between accuracy and efficiency in the maintenance of translational fidelity.

Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder

“…8 Mutations in translation elongation factors, enzymes, and ribosomal proteins involved in translational regulation are increasingly recognized as causes of human developmental and neurological disorders. 29 Mutations in genes including eukaryotic elongation factor 1a2 (EEF1A2 [MIM: 602959]), eukaryotic elongation factor 2 (EEF2 [MIM:130610]), and ribosomal proteins (RPS23 and RPL10) disrupt translation elongation and are associated with neurodevelopmental phenotypes. 29 The clinical features of affected individuals in our study show some inter-and intra-familial variation, but the core neurological features are shared.…”

Regulation of the Elongation Phase of Protein Synthesis Enhances Translation Accuracy and Modulates Lifespan

“…The production of properly made and folded proteins is crucial for normal cell function and organismal survival. Conversely, misfolded proteins can lead to a number of common and serious diseases, including several neurodegenerative disorders [1].…”

“…eEF2K Stimulation Increases the Stringency of Initiation Codon Selection(A) A549 cells were transfected with pICtest2 vectors encoding StaCFluc with different start codons (previously reported in[1]; sequences are indicated). Fluc activity was then measured, and is expressed as percentage of control (GCCAUGG) (means ± SD; n = 4 independent experiments conducted in triplicate).…”

The role of translation elongation factor eEF1 subunits in neurodevelopmental disorders

“…Fragile X syndrome, the most common inherited form of intellectual disability, results from the loss‐of‐function of a translational regulator, FMRP, and the failure to repress translation of specific mRNAs in neurons (Darnell & Klann, ). Mutations in AARSs other than VARS have been identified in numerous neurological disorders including peripheral neuropathy, epilepsy, intellectual disability, and microcephaly (Coughlin et al., ; Kapur & Ackerman, ; Kapur, Monaghan, & Ackerman, ; Kodera et al., ; Musante et al., ; Nakayama et al., ; Tsai et al., ; Zhang et al., ). Unlike VARS, these other AARSs are not associated with the eEF1B complex, and there is no evidence that the clinical mutations have arisen in neuronal‐specific transcripts.…”