Deciphering a secondary genetic code in neurons using proteomics, and codon-biased fluorophores in single neurons
Joy Goffena1, Frances Lefcort2, Yongqing Zhang3, Elin Lehrmann3, Jehremy Felig1, Joseph Walters1, Richard Buksch1, Kevin G. Becker3 and Lynn George1*
1Department of Biological and Physical Sciences, Montana State University Billings, Billings MT 59101, USA; 2Department of Cell Biology and Neuroscience, Montana State University, Bozeman MT 59717, USA; 3Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore MD 21224, USA
The genetic code consists of trinucleotide units termed codons, with each unit encoding a specific amino acid.In all species of life, the same amino acid can be encoded by up to 6 different “synonymous” codons.The reason for this redundancy remains poorly understood, although the usage of preferred codons can enhance translational efficiency and folding fidelity.The unequal usage of synonymous codons is referred to as codon bias, and the universal nature of this bias, from yeast to humans, suggests the existence of a secondary genetic code.
The neurological disease familial dysautonomia (FD) results from mutation in IKBKAP, a gene encoding an essential subunit of the Elongator complex.Since Elongator plays a key role in the translation of codon-biased genes in yeast, we investigated a translational function for Elongator in mammalian peripheral neurons, the population most devastated in FD.To address this question, we took two approaches: 1) quantification of codon-biased biosensors in single neurons; and 2) analysis of the mouse ORFeome for codon bias, multiplexed with both transcriptome and proteome analyses of over 6000 genes in control and knockout mice. Our data identify two categories of genes that rely on Elongator for proper protein production as well as specific gene functional groups that play critical roles in neuron development, function, and survival.
Funding:National Institutes of Health, R15NS090384 (L.G.), partial support provided by the Intramural Research Program of the NIH, National Institute on Aging
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