ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2014
Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease.
Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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61 citing papers in PubMed, 107 citations in OpenAlex.
- Experimental Models to Study Polyglutamine Spinocerebellar Ataxias: From Mechanisms to Therapeutic Developments.Cerebellum (London, England) · 2026Review
- Investigating the pathogenic role of calpain proteases and the therapeutic potential of their inhibition in mice modelling Machado-Joseph disease.Human molecular genetics · 2026Article
- Allosteric Modulation of Pathological Ataxin-3 Aggregation: A Path to Spinocerebellar Ataxia Type-3 Therapies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Ataxin-3 Overexpression via Adeno-associated Viral Vector Injection in the Primate Cerebellum: A Novel Model of Spinocerebellar Ataxia Type 3.Experimental neurobiology · 2025Article
- Targeting androgen receptor stability and degradation: approaches for developing a therapy for spinal and bulbar muscular atrophy.Cell communication and signaling : CCS · 2025Review
- The Role of Protein Quantity Control in Polyglutamine Spinocerebellar Ataxias.Cerebellum (London, England) · 2024Review
- Spermidine treatment: induction of autophagy but also apoptosis?Molecular brain · 2024Article
- Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3.The Journal of clinical investigation · 2024Article
- Article
- Quinones as Neuroprotective Agents.Antioxidants (Basel, Switzerland) · 2023Review
- Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IPInternational journal of molecular sciences · 2023Article
- Natural Products Targeting Hsp90 for a Concurrent Strategy in Glioblastoma and Neurodegeneration.Metabolites · 2022Review
- Cerebellar neuronal dysfunction accompanies early motor symptoms in spinocerebellar ataxia type 3.Disease models & mechanisms · 2022Article
- A quantitative high-throughput screen identifies compounds that lower expression of the SCA2-and ALS-associated gene ATXN2.The Journal of biological chemistry · 2022Article
- Microglial Depletion Has No Impact on Disease Progression in a Mouse Model of Machado-Joseph Disease.Cells · 2022Article
- Profiling Microglia in a Mouse Model of Machado-Joseph Disease.Biomedicines · 2022Article
- Plasma PolyQ-ATXN3 Levels Associate With Cerebellar Degeneration and Behavioral Abnormalities in a New AAV-Based SCA3 Mouse Model.Frontiers in cell and developmental biology · 2022Article
- Preclinical Assessment of Mesenchymal-Stem-Cell-Based Therapies in Spinocerebellar Ataxia Type 3.Biomedicines · 2021Article
- TRAP1 in Oxidative Stress and Neurodegeneration.Antioxidants (Basel, Switzerland) · 2021Review
- Unilateral Intrastriatal 6-Hydroxydopamine Lesion in Mice: A Closer Look into Non-Motor Phenotype and Glial Response.International journal of molecular sciences · 2021Article
1 more citing papers are in PubMed but not listed here.
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9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease currently with no treatment. We describe a novel mouse model of MJD which expresses mutant human ataxin-3 at near endogenous levels and manifests MJD-like motor symptoms that appear gradually and progress over time. CMVMJD135 mice show ataxin-3 intranuclear inclusions in the CNS and neurodegenerative changes in key disease regions, such as the pontine and dentate nuclei. Hsp90 inhibition has shown promising outcomes in some neurodegenerative diseases, but nothing is known about its effects in MJD. Chronic treatment of CMVMJD mice with Hsp90 inhibitor 17-DMAG resulted in a delay in the progression of their motor coordination deficits and, at 22 and 24 weeks of age, was able to rescue the uncoordination phenotype to wild-type levels; in parallel, a reduction in neuropathology was observed in treated animals. We observed limited induction of heat-shock proteins with treatment, but found evidence that 17-DMAG may be acting through autophagy, as LC3-II (both at mRNA and protein levels) and beclin-1 were induced in the brain of treated animals. This resulted in decreased levels of the mutant ataxin-3 and reduced intranuclear aggregation of this protein. Our data validate this novel mouse model as a relevant tool for the study of MJD pathogenesis and for pre-clinical studies, and show that Hsp90 inhibition is a promising therapeutic strategy for MJD.
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