ArticleScience translational medicine2016
An miRNA-mediated therapy for SCA6 blocks IRES-driven translation of the CACNA1A second cistron.
Article in Science translational medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 2 of them syntheses that pooled it.
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Who cites it
43 citing papers in PubMed, 2 syntheses or guidelines pooled it, 70 citations in OpenAlex.
- Calcium channelopathies and intellectual disability: a systematic review.Orphanet journal of rare diseases · 2021Pooled it
- Mammalian Polycistronic mRNAs and Disease.Trends in genetics : TIG · 2017Pooled it
- DB-IRES: a deep learning model based on ensemble learning for predicting internal ribosome entry sites.BMC bioinformatics · 2026Article
- Experimental Models to Study Polyglutamine Spinocerebellar Ataxias: From Mechanisms to Therapeutic Developments.Cerebellum (London, England) · 2026Review
- Resilience to Endoplasmic Reticulum Stress Mitigates Membrane Hyperexcitability Underlying Late Disease Onset in a Murine Model of SCA6.Annals of neurology · 2026Article
- The Status and Future Directions of Treatments for Polyglutamine Spinocerebellar Ataxia: A Bibliometric and Visual Analysis.Current neuropharmacology · 2026Review
- Review
- IRESeek: structure-informed deep learning method for accurate identification of internal ribosome entry sites in circular RNAs.NAR genomics and bioinformatics · 2025Article
- Endogenous Ribonucleases: Therapeutic Targeting of the Transcriptome Through Oligonucleotide-Triggered RNA Inactivation.Biomolecules · 2025Review
- Calcium channel-coupled transcription factors facilitate direct nuclear signaling.Research square · 2025Article
- Treatment of neurological pathology and inflammation in Machado-Joseph disease through in vivo self-assembled siRNA.Brain : a journal of neurology · 2025Article
- Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephaly.Nature communications · 2025Article
- DeepIRES: a hybrid deep learning model for accurate identification of internal ribosome entry sites in cellular and viral mRNAs.Briefings in bioinformatics · 2024Article
- Longitudinal MicroRNA Signature of Conversion to Psychosis.Schizophrenia bulletin · 2024Article
- Review
- Article
- Neuro-respiratory pathology in spinocerebellar ataxia.Journal of the neurological sciences · 2022Review
- HER2 c-Terminal Fragments Are Expressed via Internal Translation of the HER2 mRNA.International journal of molecular sciences · 2022Article
- Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy Development.Biomedicines · 2022Review
- Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications.Cerebellum (London, England) · 2022Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited neurodegenerative disease characterized by slowly progressive ataxia and Purkinje cell degeneration. SCA6 is caused by a polyglutamine repeat expansion within a second CACNA1A gene product, α1ACT. α1ACT expression is under the control of an internal ribosomal entry site (IRES) present within the CACNA1A coding region. Whereas SCA6 allele knock-in mice show indistinguishable phenotypes from wild-type littermates, expression of SCA6-associated α1ACT (α1ACTSCA6) driven by a Purkinje cell-specific promoter in mice produces slowly progressive ataxia and cerebellar atrophy. We developed an early-onset SCA6 mouse model using an adeno-associated virus (AAV)-based gene delivery system to ectopically express CACNA1A IRES-driven α1ACTSCA6 to test the potential of CACNA1A IRES-targeting therapies. Mice expressing AAV9-mediated CACNA1A IRES-driven α1ACTSCA6 exhibited early-onset ataxia, motor deficits, and Purkinje cell degeneration. We identified miR-3191-5p as a microRNA (miRNA) that targeted CACNA1A IRES and preferentially inhibited the CACNA1A IRES-driven translation of α1ACT in an Argonaute 4 (Ago4)-dependent manner. We found that eukaryotic initiation factors (eIFs), eIF4AII and eIF4GII, interacted with the CACNA1A IRES to enhance α1ACT translation. Ago4-bound miR-3191-5p blocked the interaction of eIF4AII and eIF4GII with the CACNA1A IRES, attenuating IRES-driven α1ACT translation. Furthermore, AAV9-mediated delivery of miR-3191-5p protected mice from the ataxia, motor deficits, and Purkinje cell degeneration caused by CACNA1A IRES-driven α1ACTSCA6 We have established proof of principle that viral delivery of an miRNA can rescue a disease phenotype through modulation of cellular IRES activity in a mouse model.
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