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Biology of tRNA and pathogenicity

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Human Glycyl-tRNA Synthetase expression in nervous tissues

In general, two different genes encode cytoplasmic and mitochondrial aminoacyl-tRNA synthetases (aaRSs). In metazoans, however, there is only one gene (GARS) for both glycyl-tRNA synthetases (GRSs). In order to understand how the two human GRSs are expressed and regulated, we used RACE PCR to identify the corresponding mRNAs and discovered two isoforms that are identical in the main coding sequence and the 3’ UTR but differ in their 5’ UTR. Our findings show that mitochondrial, cytosolic, but also endoplasmic reticulum (ER)-bound GRS expressions are highly regulated processes, involving the two mRNA isoforms (mRNA1 and mRNA2), three initiation codons, an untranslated ORF as well as an IRES structure. The cell may control the level of GRS synthesis by exploiting differential translation activities.

Summary of GARS expression from mRNA1 and mRNA2 isoforms. Translation initiation at AUG0 and AUGcyto leads to the synthesis of a short peptide and of the cytoplasmic GRS, respectively. mRNA2 decodes both the mitochondrial and cytosolic GRSs starting at AUGmito and AUGcyto, respectively.
Summary of GARS expression from mRNA1 and mRNA2 isoforms. Translation initiation at AUG0 and AUGcyto leads to the synthesis of a short peptide and of the cytoplasmic GRS, respectively. mRNA2 decodes both the mitochondrial and cytosolic GRSs starting at AUGmito and AUGcyto, respectively.

Molecular modeling, together with chemical and enzymatic probing experiments as well as Small-Angle X-ray Scattering (SAXS) of the 5’ UTR containing the IRES, will help us to determine the structural context of initiation codons and deduce precious information about the molecular mechanism that controls the specific expression of GRS at the ER.

GRS is involved in the Charcot-Marie-Tooth disease, a neurodegenerative disease. This justifies a detailed study of GRS expression in a neuronal model such as SH-SY5Y cells. We want to explore the nature of these granules and their potential role in nerve signal transduction. Furthermore, since glycine, the natural substrate of GRS, is also an inhibitory neurotransmitter, it raises the question about the involvement of GRS in glycinergic neurotransmission.