Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration

Jeong Woong Lee, Kirk Beebe, Leslie A. Nangle, Jaeseon Jang, Chantal M. Longo-Guess, Susan A. Cook, Muriel T. Davisson, John P. Sundberg, Paul Schimmel and Susan L. Ackerman ()
Additional contact information
Jeong Woong Lee: The Jackson Laboratory
Kirk Beebe: The Scripps Research Institute
Leslie A. Nangle: The Scripps Research Institute
Jaeseon Jang: The Jackson Laboratory
Chantal M. Longo-Guess: The Jackson Laboratory
Susan A. Cook: The Jackson Laboratory
Muriel T. Davisson: The Jackson Laboratory
John P. Sundberg: The Jackson Laboratory
Paul Schimmel: The Scripps Research Institute
Susan L. Ackerman: The Jackson Laboratory

Nature, 2006, vol. 443, issue 7107, 50-55

Abstract: 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.

Date: 2006
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DOI: 10.1038/nature05096

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