ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase

Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aars(sti) mutant mice resulted in an increased production of serine-mischarged tRNA(Ala) and degeneration of cerebellar Purkinje cells. By positional cloning, we identified Ankrd16, which acts epistatically with the Aars(sti) mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific, ankyrin repeat-containing protein, binds directly to the catalytic domain of AlaRS. Serine misactivated by AlaRS is captured by lysine side chains of ANKRD16, preventing the charging of serine adenylates to tRNA(Ala) and precluding serine misincorporation in nascent peptides. Deletion of Ankrd16 in the Aars(sti/sti) brain causes widespread protein aggregation and neuron loss. These results identify a novel amino acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery essential for preventing severe pathologies that arise from defects in editing.