Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD
The hexanucleotide expansion GGGGCC located in <i>C9orf72</i> gene represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Since the discovery one of the non-exclusive mechanisms of expanded hexanucleotide G<sub>4<...
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MDPI AG
2020-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/3/525 |
| _version_ | 1818190307291824128 |
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| author | Tim Božič Matja Zalar Boris Rogelj Janez Plavec Primož Šket |
| author_facet | Tim Božič Matja Zalar Boris Rogelj Janez Plavec Primož Šket |
| author_sort | Tim Božič |
| collection | DOAJ |
| description | The hexanucleotide expansion GGGGCC located in <i>C9orf72</i> gene represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Since the discovery one of the non-exclusive mechanisms of expanded hexanucleotide G<sub>4</sub>C<sub>2</sub> repeats involved in ALS and FTLD is RNA toxicity, which involves accumulation of pathological sense and antisense RNA transcripts. Formed RNA foci sequester RNA-binding proteins, causing their mislocalization and, thus, diminishing their biological function. Therefore, structures adopted by pathological RNA transcripts could have a key role in pathogenesis of ALS and FTLD. Utilizing NMR spectroscopy and complementary methods, we examined structures adopted by both guanine-rich sense and cytosine-rich antisense RNA oligonucleotides with four hexanucleotide repeats. While both oligonucleotides tend to form dimers and hairpins, the equilibrium of these structures differs with antisense oligonucleotide being more sensitive to changes in pH and sense oligonucleotide to temperature. In the presence of K<sup>+</sup> ions, guanine-rich sense RNA oligonucleotide also adopts secondary structures called G-quadruplexes. Here, we also observed, for the first time, that antisense RNA oligonucleotide forms i-motifs under specific conditions. Moreover, simultaneous presence of sense and antisense RNA oligonucleotides promotes formation of heterodimer. Studied structural diversity of sense and antisense RNA transcripts not only further depicts the complex nature of neurodegenerative diseases but also reveals potential targets for drug design in treatment of ALS and FTLD. |
| first_indexed | 2024-12-11T23:56:38Z |
| format | Article |
| id | doaj.art-3af2771e31c5486782b9fe4379684b23 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-11T23:56:38Z |
| publishDate | 2020-01-01 |
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| record_format | Article |
| series | Molecules |
| spelling | doaj.art-3af2771e31c5486782b9fe4379684b232022-12-22T00:45:20ZengMDPI AGMolecules1420-30492020-01-0125352510.3390/molecules25030525molecules25030525Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLDTim Božič0Matja Zalar1Boris Rogelj2Janez Plavec3Primož Šket4Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaSlovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaDepartment of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, SloveniaSlovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaSlovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaThe hexanucleotide expansion GGGGCC located in <i>C9orf72</i> gene represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Since the discovery one of the non-exclusive mechanisms of expanded hexanucleotide G<sub>4</sub>C<sub>2</sub> repeats involved in ALS and FTLD is RNA toxicity, which involves accumulation of pathological sense and antisense RNA transcripts. Formed RNA foci sequester RNA-binding proteins, causing their mislocalization and, thus, diminishing their biological function. Therefore, structures adopted by pathological RNA transcripts could have a key role in pathogenesis of ALS and FTLD. Utilizing NMR spectroscopy and complementary methods, we examined structures adopted by both guanine-rich sense and cytosine-rich antisense RNA oligonucleotides with four hexanucleotide repeats. While both oligonucleotides tend to form dimers and hairpins, the equilibrium of these structures differs with antisense oligonucleotide being more sensitive to changes in pH and sense oligonucleotide to temperature. In the presence of K<sup>+</sup> ions, guanine-rich sense RNA oligonucleotide also adopts secondary structures called G-quadruplexes. Here, we also observed, for the first time, that antisense RNA oligonucleotide forms i-motifs under specific conditions. Moreover, simultaneous presence of sense and antisense RNA oligonucleotides promotes formation of heterodimer. Studied structural diversity of sense and antisense RNA transcripts not only further depicts the complex nature of neurodegenerative diseases but also reveals potential targets for drug design in treatment of ALS and FTLD.https://www.mdpi.com/1420-3049/25/3/525nmrrnaalsftld<i>c9orf72</i> |
| spellingShingle | Tim Božič Matja Zalar Boris Rogelj Janez Plavec Primož Šket Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD Molecules nmr rna als ftld <i>c9orf72</i> |
| title | Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD |
| title_full | Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD |
| title_fullStr | Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD |
| title_full_unstemmed | Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD |
| title_short | Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD |
| title_sort | structural diversity of sense and antisense rna hexanucleotide repeats associated with als and ftld |
| topic | nmr rna als ftld <i>c9orf72</i> |
| url | https://www.mdpi.com/1420-3049/25/3/525 |
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