ArticleMolecular therapy : the journal of the American Society of Gene Therapy2017
Unravelling Endogenous MicroRNA System Dysfunction as a New Pathophysiological Mechanism in Machado-Joseph Disease.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 64 citations in OpenAlex.
- Importin-8 silencing reduces Ataxin-3 aggregation and alleviates Machado-Joseph disease/spinocerebellar ataxia type 3.iScience · 2026Article
- Extracellular vesicles-associated AAVs for the treatment of Machado-Joseph disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- The Dual Role of Extracellular Vesicles in Aging and Age-Related Diseases: Pathophysiology and Therapeutic Potential.International journal of nanomedicine · 2026Review
- Molecular hallmarks of neurodegeneration in polyglutamine spinocerebellar ataxias.Cell death & disease · 2025Review
- Review
- Spinocerebellar Ataxia Type 3 Pathophysiology-Implications for Translational Research and Clinical Studies.International journal of molecular sciences · 2024Review
- Cerebellar Micro-RNA Profile in a Mouse Model of Spinocerebellar Ataxia Type 2.Neurology. Genetics · 2024Article
- Therapeutic effects of engineered exosome-based miR-25 and miR-181a treatment in spinocerebellar ataxia type 3 mice by silencing ATXN3.Molecular medicine (Cambridge, Mass.) · 2023Article
- Extracellular communication between brain cells through functional transfer of Cre mRNA mediated by extracellular vesicles.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Extracellular vesicle-based delivery of silencing sequences for the treatment of Machado-Joseph disease/spinocerebellar ataxia type 3.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Extracellular communication between brain cells through functional transfer of Cre mRNA.bioRxiv : the preprint server for biology · 2023Article
- Neuro-respiratory pathology in spinocerebellar ataxia.Journal of the neurological sciences · 2022Review
- miRNA-Mediated Knockdown of ATXN3 Alleviates Molecular Disease Hallmarks in a Mouse Model for Spinocerebellar Ataxia Type 3.Nucleic acid therapeutics · 2022Article
- Allele-specific targeting of mutant ataxin-3 by antisense oligonucleotides in SCA3-iPSC-derived neurons.Molecular therapy. Nucleic acids · 2022Article
- Using genetically modified extracellular vesicles as a non-invasive strategy to evaluate brain-specific cargo.Biomaterials · 2022Article
- ULK overexpression mitigates motor deficits and neuropathology in mouse models of Machado-Joseph disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- Combinational treatments of RNA interference and extracellular vesicles in the spinocerebellar ataxia.Frontiers in molecular neuroscience · 2022Review
- New Perspectives of Gene Therapy on Polyglutamine Spinocerebellar Ataxias: From Molecular Targets to Novel Nanovectors.Pharmaceutics · 2021Review
- Mutant Ataxin-3-Containing Aggregates (MATAGGs) in Spinocerebellar Ataxia Type 3: Dynamics of the Disorder.Molecular neurobiology · 2021Review
- Current Status of Gene Therapy Research in Polyglutamine Spinocerebellar Ataxias.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Machado-Joseph disease (MJD) is a genetic neurodegenerative disease caused by an expanded polyglutamine tract within the protein ataxin-3 (ATXN3). Despite current efforts, MJD's mechanism of pathogenesis remains unclear and no disease-modifying treatment is available. Therefore, in this study, we investigated (1) the role of the 3' UTR of ATXN3, a putative microRNA (miRNA) target, (2) whether miRNA biogenesis and machinery are dysfunctional in MJD, and (3) which specific miRNAs target ATXN3-3' UTR and whether they can alleviate MJD neuropathology in vivo. Our results demonstrate that endogenous miRNAs, by targeting sequences in the 3' UTR, robustly reduce ATXN3 expression and aggregation in vitro and neurodegeneration and neuroinflammation in vivo. Importantly, we found an abnormal MJD-associated downregulation of genes involved in miRNA biogenesis and silencing activity. Finally, we identified three miRNAs-mir-9, mir-181a, and mir-494-that interact with the ATXN3-3' UTR and whose expression is dysregulated in human MJD neurons and in other MJD cell and animal models. Furthermore, overexpression of these miRNAs in mice resulted in reduction of mutATXN3 levels, aggregate counts, and neuronal dysfunction. Altogether, these findings indicate that endogenous miRNAs and the 3' UTR of ATXN3 play a crucial role in MJD pathogenesis and provide a promising opportunity for MJD treatment.
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