Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice
Spinocerebellar ataxia type 3 (SCA3) is a currently incurable neurodegenerative disorder caused by a CAG triplet expansion in exon 10 of the ATXN3 gene. The resultant expanded polyglutamine stretch in the mutant ataxin-3 protein causes a gain of toxic function, which eventually leads to neurodegener...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-09-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253117302056 |
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| author | Lodewijk J.A. Toonen Frank Rigo Haico van Attikum Willeke M.C. van Roon-Mom |
| author_facet | Lodewijk J.A. Toonen Frank Rigo Haico van Attikum Willeke M.C. van Roon-Mom |
| author_sort | Lodewijk J.A. Toonen |
| collection | DOAJ |
| description | Spinocerebellar ataxia type 3 (SCA3) is a currently incurable neurodegenerative disorder caused by a CAG triplet expansion in exon 10 of the ATXN3 gene. The resultant expanded polyglutamine stretch in the mutant ataxin-3 protein causes a gain of toxic function, which eventually leads to neurodegeneration. One important function of ataxin-3 is its involvement in the proteasomal protein degradation pathway, and long-term downregulation of the protein may therefore not be desirable. In the current study, we made use of antisense oligonucleotides to mask predicted exonic splicing signals, resulting in exon 10 skipping from ATXN3 pre-mRNA. This led to formation of a truncated ataxin-3 protein lacking the toxic polyglutamine expansion, but retaining its ubiquitin binding and cleavage function. Repeated intracerebroventricular injections of the antisense oligonucleotides in a SCA3 mouse model led to exon skipping and formation of the modified ataxin-3 protein throughout the mouse brain. Exon skipping was long lasting, with the modified protein being detectable for at least 2.5 months after antisense oligonucleotide injection. A reduction in insoluble ataxin-3 and nuclear accumulation was observed following antisense oligonucleotide treatment, indicating a beneficial effect on pathogenicity. Together, these data suggest that exon 10 skipping is a promising therapeutic approach for SCA3. Keywords: antisense oligonucleotides, spinocerebellar ataxia type 3, exon skipping, ataxin-3, ATXN3, SCA3, Machado-Joseph disease |
| first_indexed | 2024-04-12T23:08:17Z |
| format | Article |
| id | doaj.art-bb2a414e047f4de8ac818fd07f532d5d |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-12T23:08:17Z |
| publishDate | 2017-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-bb2a414e047f4de8ac818fd07f532d5d2022-12-22T03:12:52ZengElsevierMolecular Therapy: Nucleic Acids2162-25312017-09-018232242Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 MiceLodewijk J.A. Toonen0Frank Rigo1Haico van Attikum2Willeke M.C. van Roon-Mom3Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, the NetherlandsIonis Pharmaceuticals, Carlsbad, CA 92008, USADepartment of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, the NetherlandsDepartment of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, the Netherlands; Corresponding author: Willeke M.C. van Roon-Mom, Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, the Netherlands.Spinocerebellar ataxia type 3 (SCA3) is a currently incurable neurodegenerative disorder caused by a CAG triplet expansion in exon 10 of the ATXN3 gene. The resultant expanded polyglutamine stretch in the mutant ataxin-3 protein causes a gain of toxic function, which eventually leads to neurodegeneration. One important function of ataxin-3 is its involvement in the proteasomal protein degradation pathway, and long-term downregulation of the protein may therefore not be desirable. In the current study, we made use of antisense oligonucleotides to mask predicted exonic splicing signals, resulting in exon 10 skipping from ATXN3 pre-mRNA. This led to formation of a truncated ataxin-3 protein lacking the toxic polyglutamine expansion, but retaining its ubiquitin binding and cleavage function. Repeated intracerebroventricular injections of the antisense oligonucleotides in a SCA3 mouse model led to exon skipping and formation of the modified ataxin-3 protein throughout the mouse brain. Exon skipping was long lasting, with the modified protein being detectable for at least 2.5 months after antisense oligonucleotide injection. A reduction in insoluble ataxin-3 and nuclear accumulation was observed following antisense oligonucleotide treatment, indicating a beneficial effect on pathogenicity. Together, these data suggest that exon 10 skipping is a promising therapeutic approach for SCA3. Keywords: antisense oligonucleotides, spinocerebellar ataxia type 3, exon skipping, ataxin-3, ATXN3, SCA3, Machado-Joseph diseasehttp://www.sciencedirect.com/science/article/pii/S2162253117302056 |
| spellingShingle | Lodewijk J.A. Toonen Frank Rigo Haico van Attikum Willeke M.C. van Roon-Mom Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice Molecular Therapy: Nucleic Acids |
| title | Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice |
| title_full | Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice |
| title_fullStr | Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice |
| title_full_unstemmed | Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice |
| title_short | Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice |
| title_sort | antisense oligonucleotide mediated removal of the polyglutamine repeat in spinocerebellar ataxia type 3 mice |
| url | http://www.sciencedirect.com/science/article/pii/S2162253117302056 |
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