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Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts
- Source :
- Human Molecular Genetics. 14:2649-2660
- Publication Year :
- 2005
- Publisher :
- Oxford University Press (OUP), 2005.
-
Abstract
- The expanded CAG tract diseases are a heterogeneous group of late-onset neurodegenerative disorders characterized by the accumulation of insoluble protein material and premature neuronal cell death. Recent work has provided support for several mechanisms that may account for neurodegeneration, but no unifying mechanism has emerged. We have previously demonstrated that in SCA3, the expanded CAG tract in the MJD-1 transcript is prone to frameshifting, which may lead to the production of polyalanine-containing proteins. To further examine the occurrence of frameshifting and understand its mechanism and possible role in pathogenesis, a cellular model was established. We show that this phenomenon results from ribosomal slippage to the -1 frame exclusively, that ribosomal frameshifting depends on the presence of long CAG tracts and that polyalanine-frameshifted proteins may enhance polyglutamine-associated toxicity, possibly contributing to pathogenesis. Finally, we present evidence that anisomycin, a ribosome-interacting drug that reduces -1 frameshifting, also reduces toxicity, suggesting a new therapeutic opportunity for these disorders.
- Subjects :
- congenital, hereditary, and neonatal diseases and abnormalities
Green Fluorescent Proteins
Immunoblotting
Molecular Sequence Data
Nerve Tissue Proteins
Biology
Ribosome
chemistry.chemical_compound
Genetics
medicine
Humans
Amino Acid Sequence
Nuclear protein
Ataxin-3
Frameshift Mutation
Molecular Biology
Cells, Cultured
Genetics (clinical)
Anisomycin
DNA Primers
Translational frameshift
Neurodegeneration
Frameshifting, Ribosomal
Nuclear Proteins
Sequence Analysis, DNA
General Medicine
Flow Cytometry
medicine.disease
Immunohistochemistry
Repressor Proteins
chemistry
Heredodegenerative Disorders, Nervous System
Peptides
Trinucleotide Repeat Expansion
Neuron death
Trinucleotide repeat expansion
Machado–Joseph disease
Plasmids
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....ea0f242d2057b7de0b16b34c96c4271e