Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration

Misfolded proteins are associated with several pathological conditions including neurodegeneration. Although some of these abnormally folded proteins result from mutations in genes encoding disease-associated proteins (for example, repeat-expansion diseases), more general mechanisms that lead to misfolded proteins in neurons remain largely unknown. Here we demonstrate that low levels of mischarged transfer RNAs (tRNAs) can lead to an intracellular accumulation of misfolded proteins in neurons. These accumulations are accompanied by upregulation of cytoplasmic protein chaperones and by induction of the unfolded protein response. We report that the mouse sticky mutation, which causes cerebellar Purkinje cell loss and ataxia, is a missense mutation in the editing domain of the alanyl-tRNA synthetase gene that compromises the proofreading activity of this enzyme during aminoacylation of tRNAs. These findings demonstrate that disruption of translational fidelity in terminally differentiated neurons leads to the accumulation of misfolded proteins and cell death, and provide a novel mechanism underlying neurodegeneration. In mice with the sticky mutation, the cells that are involved in motor coordination degenerate, due to a single nucleotide change in the enzyme called alanyl-tRNA synthetase. This demonstrates the potentially catastrophic consequences of small changes in the fidelity of translation. A sticky wicket Until recently the 'sticky' mouse mutation was known mainly for the unkempt appearance of its fur. It gradually loses its hair too. At 6 weeks of age it has mild tremors when excited and by week 8 it begins to suffer from progressive ataxia. This coincides with the loss of Purkinje cells in the cerebellum. The sticky mutation has now been identified as a single nucleotide change in alanyl-transfer RNA synthetase. The subsequent reduced fidelity of translation and protein misfolding causes cell death as abnormal proteins accumulate in the neurons. Many human diseases are associated with protein misfolding and neural loss, and the properties of the sticky mice suggest that some of these diseases could be due to mutations that disrupt tRNA synthetase enzymes.