title: Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration.
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.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
authors.forename: Jeong Woong
authors.initials: JW
authors.lastname: Lee
authors.forename: Kirk
authors.initials: K
authors.lastname: Beebe
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Nangle
authors.forename: Jaeseon
authors.initials: J
authors.lastname: Jang
authors.forename: Chantal M
authors.initials: CM
authors.lastname: Longo-Guess
authors.forename: Susan A
authors.initials: SA
authors.lastname: Cook
authors.forename: Muriel T
authors.initials: MT
authors.lastname: Davisson
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ackerman
mesh_terms: D000107:Acetylation; D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000412:Alanine-tRNA Ligase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002384:Catalysis; D004926:Escherichia coli / Q000235:genetics; D005347:Fibroblasts; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics; D010641:Phenotype; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D012344:RNA, Transfer, Ala / Q000235:genetics; D012694:Serine / Q000235:genetics / Q000378:metabolism
chemical_list: D012344:RNA, Transfer, Ala; D012694:Serine; D000412:Alanine-tRNA Ligase; D000409:Alanine