Defeating peripheral neuropathy
The mechanisms underlying peripheral neuropathies are not well understood. Spaulding
et al
. studied mouse models of the inherited Charcot-Marie-Tooth (CMT) disease, which is caused by mutations in transfer RNA (tRNA) synthetases. Changes in gene expression and the rate of protein synthesis in neurons in the spinal cord triggered the cell stress response activated by the protein sensor GCN2. When GCN2 was genetically deleted or inhibited with drugs, the stress response was blocked, and the neuropathy was much milder. Zuko
et al
. found that mutant glycyl-tRNA synthetases bind tRNA
Gly
but fail to release it, thus depleting the cellular tRNA
Gly
pool. This process caused stalling of translating ribosomes on glycine codons and activated the integrated stress response. Transgenic tRNA
Gly
overexpression prevented peripheral neuropathy and protein synthesis defects in mouse and fruit fly models. Thus, elevating tRNA
Gly
levels or targeting GCN2 may have therapeutic potential for this currently untreatable disease (see the Perspective by Mellado and Willis). —SMH
Epistasis refers to the dependence of a mutation on other mutation(s) and the genetic context in general. In the context of human disorders, epistasis complicates the spectrum of disease symptoms and has been proposed as a major contributor to variations in disease outcome. The nonadditive relationship between mutations and the lack of complete understanding of the underlying physiological effects limit our ability to predict phenotypic outcome. Here, we report positive epistasis between intragenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)—the gene responsible for cystic fibrosis (CF) pathology. We identified a synonymous single-nucleotide polymorphism (sSNP) that is invariant for the CFTR amino acid sequence but inverts translation speed at the affected codon. This sSNP in cis exhibits positive epistatic effects on some CF disease–causing missense mutations. Individually, both mutations alter CFTR structure and function, yet when combined, they lead to enhanced protein expression and activity. The most robust effect was observed when the sSNP was present in combination with missense mutations that, along with the primary amino acid change, also alter the speed of translation at the affected codon. Functional studies revealed that synergistic alteration in ribosomal velocity is the underlying mechanism; alteration of translation speed likely increases the time window for establishing crucial domain–domain interactions that are otherwise perturbed by each individual mutation.
Stress granules (SGs) are membrane-less condensates composed of RNA and protein that assemble in response to stress stimuli and disassemble when stress is lifted. Both assembly and disassembly are tightly controlled processes, yet, it remains elusive whether mRNAs in SGs completely recover for translation following stress relief. Using RNA-seq of translating fractions in human cell line, we found that higher fraction of the m
6
A-modified mRNAs recovered for translation compared to unmodified mRNAs, i.e. 95% vs 84%, respectively. Considering structural mRNA analysis, we found that the m
6
A modification enhances structuring at nucleotides in its close vicinity. Our results suggest that SG-sequestered mRNAs disassemble nearly completely from SGs and the m
6
A modification may display some advantage to the mRNAs in their recovery for translation likely by m
6
A-driven structural stabilization.
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