ArticleNeurobiology of disease2021
Targeting the VCP-binding motif of ataxin-3 improves phenotypes in Drosophila models of Spinocerebellar Ataxia Type 3.
Article in Neurobiology of disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 13 citations in OpenAlex.
- Mapping the Disrupted Connectome in Spinocerebellar Ataxia Type 3: A Network-Based Statistics Study Identifying Novel Therapeutic Targets for Neuromodulation.CNS neuroscience & therapeutics · 2026Article
- Insights into dentatorubral-pallidoluysian atrophy from a new Drosophila model of disease.Neurobiology of disease · 2025Article
- Spinocerebellar Ataxia Type 3 Pathophysiology-Implications for Translational Research and Clinical Studies.International journal of molecular sciences · 2024Review
- A phenotypically robust model of spinal and bulbar muscular atrophy in Drosophila.Journal of neuroscience research · 2024Article
- Lysine 117 on ataxin-3 modulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.Journal of the neurological sciences · 2023Article
- Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases.Molecular neurodegeneration · 2023Review
- Review
- Article
- A survey of protein interactions and posttranslational modifications that influence the polyglutamine diseases.Frontiers in molecular neuroscience · 2022Review
- Ubiquitin-binding site 1 of pathogenic ataxin-3 regulates its toxicity inFrontiers in neuroscience · 2022Article
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Authors and funding
7 authors at 1 institution in 1 country.
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Abstract
Of the family of polyglutamine (polyQ) neurodegenerative diseases, Spinocerebellar Ataxia Type 3 (SCA3) is the most common. Like other polyQ diseases, SCA3 stems from abnormal expansions in the CAG triplet repeat of its disease gene resulting in elongated polyQ repeats within its protein, ataxin-3. Various ataxin-3 protein domains contribute to its toxicity, including the valosin-containing protein (VCP)-binding motif (VBM). We previously reported that VCP, a homo-hexameric protein, enhances pathogenic ataxin-3 aggregation and exacerbates its toxicity. These findings led us to explore the impact of targeting the SCA3 protein by utilizing a decoy protein comprising the N-terminus of VCP (N-VCP) that binds ataxin-3's VBM. The notion was that N-VCP would reduce binding of ataxin-3 to VCP, decreasing its aggregation and toxicity. We found that expression of N-VCP in Drosophila melanogaster models of SCA3 ameliorated various phenotypes, coincident with reduced ataxin-3 aggregation. This protective effect was specific to pathogenic ataxin-3 and depended on its VBM. Increasing the amount of N-VCP resulted in further phenotype improvement. Our work highlights the protective potential of targeting the VCP-ataxin-3 interaction in SCA3, a key finding in the search for therapeutic opportunities for this incurable disorder.
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