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Oligonucleotide-based strategies to combat polyglutamine diseases.

Fiszer A, Krzyzosiak WJ - Nucleic Acids Res. (2014)

Bottom Line: The latter include targeting SNP variants associated with mutations or targeting the pathologically expanded CAG repeat directly.We compare gene silencing effectors of various types in a number of aspects, including their design, efficiency in cell culture experiments and pre-clinical testing.We discuss advantages, current limitations and perspectives of various ON-based strategies used to treat polyQ diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.

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Toxic entities in the pathogenesis of polyQ diseases. The main products of the mutant gene are the mutant transcript containing the expanded CAG repeats and the mutant protein containing the expanded polyQ tract. The hallmarks of primary toxic events are nuclear aggregates containing mutant RNAs (CAG foci) or mutant proteins (full length or fragments). The interactions and events leading to the production of additional toxic entities from the mutant transcript and mutant protein are indicated. The antisense transcription of the mutant polyQ gene may result in transcripts containing expanded CUG repeats. siRNAs generated by the RNase Dicer from the expanded tracts may interact with complementary sequences in the transcriptome and cause the downregulation of the expression of numerous genes. Aberrant translation may lead to peptides containing polyA, polyS or polyQ tracts. See the text for more details.
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Figure 1: Toxic entities in the pathogenesis of polyQ diseases. The main products of the mutant gene are the mutant transcript containing the expanded CAG repeats and the mutant protein containing the expanded polyQ tract. The hallmarks of primary toxic events are nuclear aggregates containing mutant RNAs (CAG foci) or mutant proteins (full length or fragments). The interactions and events leading to the production of additional toxic entities from the mutant transcript and mutant protein are indicated. The antisense transcription of the mutant polyQ gene may result in transcripts containing expanded CUG repeats. siRNAs generated by the RNase Dicer from the expanded tracts may interact with complementary sequences in the transcriptome and cause the downregulation of the expression of numerous genes. Aberrant translation may lead to peptides containing polyA, polyS or polyQ tracts. See the text for more details.

Mentions: In the traditional view of gene expression, the expanded CAG*CTG repeats present in mutant polyQ disease genes are transcribed into CAG repeats in RNA and translated into polyQ tracts in the encoded proteins (Figure 1). The abnormal protein–protein interactions triggered by mutant proteins were long thought to be the only factor responsible for the pathogenesis of polyQ diseases. In recent years, however, several examples of mutant transcript toxicity were demonstrated, and additional toxic RNA and protein entities were identified.


Oligonucleotide-based strategies to combat polyglutamine diseases.

Fiszer A, Krzyzosiak WJ - Nucleic Acids Res. (2014)

Toxic entities in the pathogenesis of polyQ diseases. The main products of the mutant gene are the mutant transcript containing the expanded CAG repeats and the mutant protein containing the expanded polyQ tract. The hallmarks of primary toxic events are nuclear aggregates containing mutant RNAs (CAG foci) or mutant proteins (full length or fragments). The interactions and events leading to the production of additional toxic entities from the mutant transcript and mutant protein are indicated. The antisense transcription of the mutant polyQ gene may result in transcripts containing expanded CUG repeats. siRNAs generated by the RNase Dicer from the expanded tracts may interact with complementary sequences in the transcriptome and cause the downregulation of the expression of numerous genes. Aberrant translation may lead to peptides containing polyA, polyS or polyQ tracts. See the text for more details.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4066792&req=5

Figure 1: Toxic entities in the pathogenesis of polyQ diseases. The main products of the mutant gene are the mutant transcript containing the expanded CAG repeats and the mutant protein containing the expanded polyQ tract. The hallmarks of primary toxic events are nuclear aggregates containing mutant RNAs (CAG foci) or mutant proteins (full length or fragments). The interactions and events leading to the production of additional toxic entities from the mutant transcript and mutant protein are indicated. The antisense transcription of the mutant polyQ gene may result in transcripts containing expanded CUG repeats. siRNAs generated by the RNase Dicer from the expanded tracts may interact with complementary sequences in the transcriptome and cause the downregulation of the expression of numerous genes. Aberrant translation may lead to peptides containing polyA, polyS or polyQ tracts. See the text for more details.
Mentions: In the traditional view of gene expression, the expanded CAG*CTG repeats present in mutant polyQ disease genes are transcribed into CAG repeats in RNA and translated into polyQ tracts in the encoded proteins (Figure 1). The abnormal protein–protein interactions triggered by mutant proteins were long thought to be the only factor responsible for the pathogenesis of polyQ diseases. In recent years, however, several examples of mutant transcript toxicity were demonstrated, and additional toxic RNA and protein entities were identified.

Bottom Line: The latter include targeting SNP variants associated with mutations or targeting the pathologically expanded CAG repeat directly.We compare gene silencing effectors of various types in a number of aspects, including their design, efficiency in cell culture experiments and pre-clinical testing.We discuss advantages, current limitations and perspectives of various ON-based strategies used to treat polyQ diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.

Show MeSH
Related in: MedlinePlus