ArticleNeurobiology of disease2018
Toxicity and aggregation of the polyglutamine disease protein, ataxin-3 is regulated by its binding to VCP/p97 in Drosophila melanogaster.
Article in Neurobiology of disease, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 29 citations in OpenAlex.
- Insights into dentatorubral-pallidoluysian atrophy from a new Drosophila model of disease.Neurobiology of disease · 2025Article
- Ubiquitin-Proteasome-Mediated Protein Degradation and Disorders of the Central Nervous System.International journal of molecular sciences · 2025Review
- Progressive degeneration in a new Drosophila model of spinocerebellar ataxia type 7.Scientific reports · 2024Article
- Spinocerebellar Ataxia Type 3 Pathophysiology-Implications for Translational Research and Clinical Studies.International journal of molecular sciences · 2024Review
- Progressive degeneration in a newResearch square · 2023Article
- Lysine 117 on ataxin-3 modulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.Journal of the neurological sciences · 2023Article
- Phenotypic defects from the expression of wild-type and pathogenic TATA-binding proteins in new Drosophila models of Spinocerebellar Ataxia Type 17.G3 (Bethesda, Md.) · 2023Article
- Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases.Molecular neurodegeneration · 2023Review
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- Endurance exercise ameliorates phenotypes ineLife · 2022Article
- Ubiquitin-binding site 1 of pathogenic ataxin-3 regulates its toxicity inFrontiers in neuroscience · 2022Article
- A survey of protein interactions and posttranslational modifications that influence the polyglutamine diseases.Frontiers in molecular neuroscience · 2022Review
- Targeting the VCP-binding motif of ataxin-3 improves phenotypes in Drosophila models of Spinocerebellar Ataxia Type 3.Neurobiology of disease · 2021Article
- Mutant Ataxin-3-Containing Aggregates (MATAGGs) in Spinocerebellar Ataxia Type 3: Dynamics of the Disorder.Molecular neurobiology · 2021Review
- The Deubiquitinating Enzyme Ataxin-3 Regulates Ciliogenesis and Phagocytosis in the Retina.Cell reports · 2020Article
- Degron capability of the hydrophobic C-terminus of the polyglutamine disease protein, ataxin-3.Journal of neuroscience research · 2020Article
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- Article
- Druggable genome screen identifies new regulators of the abundance and toxicity of ATXN3, the Spinocerebellar Ataxia type 3 disease protein.Neurobiology of disease · 2020Article
- Differential toxicity of ataxin-3 isoforms in Drosophila models of Spinocerebellar Ataxia Type 3.Neurobiology of disease · 2019Article
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Authors and funding
4 authors at 1 institution in 1 country.
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Abstract
Among the nine dominantly inherited, age-dependent neurodegenerative diseases caused by abnormal expansion in the polyglutamine (polyQ) repeat of otherwise unrelated proteins is Spinocerebellar Ataxia Type 3 (SCA3). SCA3 is caused by polyQ expansion in the deubiquitinase (DUB), ataxin-3. Molecular sequelae related to SCA3 remain unclear. Here, we sought to understand the role of protein context in SCA3 by focusing on the interaction between this DUB and Valosin-Containing Protein (VCP). VCP is bound directly by ataxin-3 through an arginine-rich area preceding the polyQ repeat. We examined the importance of this interaction in ataxin-3-dependent degeneration in Drosophila melanogaster. Our assays with new isogenic fly lines expressing pathogenic ataxin-3 with an intact or mutated VCP-binding site show that disrupting the ataxin-3-VCP interaction delays the aggregation of the toxic protein in vivo. Importantly, early on flies that express pathogenic ataxin-3 with a mutated VCP-binding site are indistinguishable from flies that do not express any SCA3 protein. Also, reducing levels of VCP through RNA-interference has a similar, protective effect to mutating the VCP-binding site of pathogenic ataxin-3. Based on in vivo pulse-chases, aggregated species of ataxin-3 are highly stable, in a manner independent of VCP-binding. Collectively, our results highlight an important role for the ataxin-3-VCP interaction in SCA3, based on a model that posits a seeding effect from VCP on pathogenic ataxin-3 aggregation and subsequent toxicity.
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