Polyglutamine Ataxias: Our Current Molecular Understanding and What the Future Holds for Antisense Therapies
Abstract
:1. Introduction
2. The CAG Expansion
3. Common Pathological Features
3.1. Protein Aggregation
3.2. Mitochondrial Dysfunction and Oxidative Stress
3.3. Proteasomal and Autophagy Impairment
3.4. RNA Toxicity
3.5. Neuroinflammation
4. Spinocerebellar Ataxia Type 1 (SCA1)
5. Spinocerebellar Ataxia Type 2 (SCA2)
6. Spinocerebellar Ataxia Type 3 (SCA3)
7. Spinocerebellar Ataxia Type 6 (SCA6)
8. Spinocerebellar Ataxia Type 7 (SCA7)
9. Spinocerebellar Ataxia Type 17 (SCA17)
10. Brief Background into Antisense Therapeutics
10.1. RNaseH Degradation of a Targeted RNA Transcript
10.2. Splice Switching
11. Antisense Therapeutics for SCAs
11.1. SCA1
11.2. SCA2
11.3. SCA3
11.4. SCA7
12. A History and Outcome of Recent Huntington’s Disease Clinical Trial
13. Conclusions and Future Potential
Author Contributions
Funding
Conflicts of Interest
References
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Disease | Causative Gene | Normal Gene Function * | PolyQ Location | Healthy Repeat Range | Pre-Mutation Repeat Range | Pathogenetic Repeat Range |
---|---|---|---|---|---|---|
SCA1 MIM #164400 | ATXN1 MIM #601556 | RNA metabolism and transcriptional repression | Exon 7 | 6–35 | 36–40 | 41–89 |
SCA2 MIM #183090 | ATXN2 MIM #601517 | Transcriptional repression and RNA metabolism | Exon 1 | 17–29 | 30–36 | 37–100+ |
SCA3 MIM #109150 | ATXN3 MIM #607047 | Deubiquitination and proteasomal protein degradation | Exon 10 | 7–44 | 45–54 | 55–89 |
SCA6 MIM #183086 | CACNA1A MIM #601011 | Gives rise to P/Q calcium channels and neurotransmitter release from presynaptic terminals | Exon 47 | 4–18 | 19–20 | 21–30 |
SCA7 MIM #164500 | ATXN7 MIM #607640 | Mediates the interaction between the CRX and STAGA complex | Exon 3 | 7–19 | 20–35 | 36–400+ |
SCA17 MIM #607136 | TBP MIM #600075 | General transcription factor and mediates the initiation of transcription through TFIID binding to the TAT box | Exon 3 | 25–42 | 43–46 | 47–66 |
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McIntosh, C.S.; Li, D.; Wilton, S.D.; Aung-Htut, M.T. Polyglutamine Ataxias: Our Current Molecular Understanding and What the Future Holds for Antisense Therapies. Biomedicines 2021, 9, 1499. https://doi.org/10.3390/biomedicines9111499
McIntosh CS, Li D, Wilton SD, Aung-Htut MT. Polyglutamine Ataxias: Our Current Molecular Understanding and What the Future Holds for Antisense Therapies. Biomedicines. 2021; 9(11):1499. https://doi.org/10.3390/biomedicines9111499
Chicago/Turabian StyleMcIntosh, Craig S., Dunhui Li, Steve D. Wilton, and May T. Aung-Htut. 2021. "Polyglutamine Ataxias: Our Current Molecular Understanding and What the Future Holds for Antisense Therapies" Biomedicines 9, no. 11: 1499. https://doi.org/10.3390/biomedicines9111499