Page 13 - Read Online

Franz et al. J Transl Genet Genom 2020;4:50-70 I https://doi.org/10.20517/jtgg.2020.13 Page 51

INTRODUCTION
Cognitive impairment features among the most important problems in healthcare, one prominent example
being intellectual disability (ID) with a prevalence between 1% and 3%. The majority of severe forms of
ID have specific yet very heterogeneous genetic causes, including numerous X-chromosomal as well as
autosomal gene defects and disease-causing copy-number variants [1-5] . Thus, with the exception of a few
[7]
[6]
more prominent syndromes (for pertinent reviews see e.g., Salcedo-Arellano et al. , 2020, Glasson et al. ,
[8]
2020, Antonarakis et al. , 2020), individual genes only account for an often extremely low proportion of
cases.
Accumulating evidence, however, indicates that while there are no major players on a genetic level, there are
functional contexts or pathways that play a prominent role in the etiology of hereditary forms of ID and are
thus of major importance for the development and maintenance of higher cognitive functions. One such
feature is the molecular and functional integrity of transfer RNA (tRNA), and we and others have recently
put forward the notion that a full as well as a fully functional complement of tRNAs is vital for human
cognition [9,10] . This is corroborated by the results of a survey of the recent literature, which shows a steep
increase in the number of articles featuring tRNA-related issues in the context of impaired human cognition
over the last few years [Figure 1]. In support of the hypothesis that tRNAs play a major role in the basis of
human cognitive features, our review aims to provide a synopsis of the presently available literature on tRNA
modifiers and aminoacyl-tRNA synthetases (ARSs) that were found to play a role in the etiology of cognitive
dysfunction.

tRNA STRUCTURE AND FUNCTION
tRNAs are important mediator molecules that facilitate the reading and translation process of the triplet
[11]
genetic code from messenger RNA (mRNA) to corresponding polypeptides during protein biosynthesis .
[12]
The human genome contains more than 500 tRNA genes ; however, tRNA expression is cell- and tissue-
[13]
specific and approximately half of the genes are not or poorly expressed .
The typical tRNA secondary structure, consisting of hydrogen-bonded stems and associated loops, is shown
in Figure 2. This results in a complex three-dimensional folding of the molecule, so that in their tertiary
structure all tRNAs assume an L-shape. The 3’ end of this structure serves as the amino acid attachment site.
The anticodon loop, which is exposed at the tip of the L-shape, is used for mRNA codon recognition. Base
pairing with the first and third residue of the anticodon can be flexible so that some tRNAs can recognize
various codons.

The translation of proteins from their coding mRNAs, where tRNAs play a central role, is an absolutely
essential process. It begins with the formation of the pre-initiation complex, which is formed from the
Met
40S subunit of a ribosome, the initiator tRNA , GTP and various initiation factors. mRNA binds to this
complex at its 5’ end and translation is initiated when a start codon (AUG) is recognized. Elongation starts
with the binding of the initiator tRNA to the peptidyl site of the ribosome, the second binding site of the
ribosome, and the aminoacyl site is then occupied by the next tRNA. A peptide bond is formed between
the methionine of the initiator tRNA and the amino acid of the following tRNA. The ribosome then moves
one position further on the mRNA and binds another aminoacylated tRNA. This elongation continues
[14]
until a stop codon is reached, after which the polypeptide leaves the ribosome . This happens at a rate of
approximately ten tRNAs per second.

To ensure that protein synthesis runs smoothly, tRNA molecules are chemically modified [15-18] . These
alterations include methylation (guanosine → 7-methylguanosine), deamination (adenine → inosine), Sulfur
substitution (uridine → 4-thiouridine), intramolecular rearrangements (uridine → pseudouridine) and the
saturation of existing double bonds (uridine → dihydrouridine). Some of the non-standard ribonucleosides