Figure 3. tRNA Processing in Health and in Neurodegeneration.

Precursor tRNAs undergo numerous processing steps in order to form mature tRNAs that can be charged by their cognate aminoacyl tRNA synthetases. A small subset of tRNAs contain introns that are removed by splicing, and the tRNA splicing endonuclease (TSEN) complex, along with the kinase CLP1, play an essential role in this process. Disease-linked mutations in TSEN subunits or in CLP1 disrupt the assembly and activity of the TSEN/CLP1 complex, impairing the processing of precursor tRNAs. This leads to the accumulation of intermediate fragments, and in some cases, a reduction in the level of mature tRNA available for charging. Mature tRNAs can be cleaved by a stress-activated ribonuclease, angiogenin (ANG). Cleavage within the anticodon loop releases tRNA halves, and specific 5’ tRNA halves can displace the eukaryotic initiation factors (eIF) 4G and eIF4A from the 7-methylguanosine (m⁷G) cap of the mRNA, repressing translation initiation. ANG can also remove the CCA tail (added by TRNT1) from the 3’ end of the tRNA, preventing charging by the synthetase, and thus inhibiting translation elongation.