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Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration
- Source :
- Nature. 443:50-55
- Publication Year :
- 2006
- Publisher :
- Springer Science and Business Media LLC, 2006.
-
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.
- Subjects :
- Models, Molecular
Protein Folding
Molecular Sequence Data
RNA, Transfer, Ala
Cerebellar Purkinje cell
Biology
medicine.disease_cause
Catalysis
Mice
Purkinje Cells
JUNQ and IPOD
Escherichia coli
Serine
medicine
Animals
Humans
Mutation
Alanine
Multidisciplinary
Alanine-tRNA Ligase
Neurodegeneration
Acetylation
Neurodegenerative Diseases
Fibroblasts
medicine.disease
Mice, Mutant Strains
Protein Structure, Tertiary
Mice, Inbred C57BL
Phenotype
Aggresome
Biochemistry
Transfer RNA
Unfolded protein response
Protein folding
Subjects
Details
- ISSN :
- 14764687 and 00280836
- Volume :
- 443
- Database :
- OpenAIRE
- Journal :
- Nature
- Accession number :
- edsair.doi.dedup.....1e902e72a5010ac9bca47d756ee503e5