Abstract

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.

1. The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA
2. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
3. Howard Hughes Medical Institute, Bar Harbor, Maine 04609, USA
4. Present address: Department of Bioelectronics and Bioinformatics, Korea Bio Polytechnic College, Chungnam 320-905, Korea

Correspondence to: Susan L. Ackerman^1,3 Correspondence and requests for materials should be addressed to S.L.A. (Email: susan.ackerman@jax.org). The sequence for mouse Aars has been deposited in GenBank under the accession number AY223875; sequence-tagged sites (STSs) for D8SlacCA1 (DQ386090), D8SlacCA2 (DQ386088) and D8SlacCA3 (DQ386089) can also be found in GenBank

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