ArticlePLoS genetics2013
Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 79 citations in OpenAlex.
- High-throughput screening approach identifies substrate-selective Hsp104 variants that counter amyloid seeding with diminished off-target effects.Molecular cell · 2026Article
- Design principles to tailor Hsp104 therapeutics.Cell reports · 2024Article
- The Role of Protein Quantity Control in Polyglutamine Spinocerebellar Ataxias.Cerebellum (London, England) · 2024Review
- Design principles to tailor Hsp104 therapeutics.bioRxiv : the preprint server for biology · 2024Article
- Article
- Tuning Hsp104 specificity to selectively detoxify α-synuclein.Molecular cell · 2023Article
- Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3.Cell reports · 2022Article
- Hsp104 N-terminal domain interaction with substrates plays a regulatory role in protein disaggregation.The FEBS journal · 2022Article
- Modifier pathways in polyglutamine (PolyQ) diseases: from genetic screens to drug targets.Cellular and molecular life sciences : CMLS · 2022Review
- AAA+ proteins: one motor, multiple ways to work.Biochemical Society transactions · 2022Review
- Molecular mechanisms of amyloid disaggregation.Journal of advanced research · 2022Review
- Ackee (Oxidative medicine and cellular longevity · 2022Article
- Amyloid Fragmentation and Disaggregation in Yeast and Animals.Biomolecules · 2021Review
- Huntingtin Polyglutamine Fragments Are a Substrate for Hsp104 in Saccharomyces cerevisiae.Molecular and cellular biology · 2021Article
- Protein Aggregation and Disaggregation in Cells and Development.Journal of molecular biology · 2021Review
- Drivers of Hsp104 potentiation revealed by scanning mutagenesis of the middle domain.Protein science : a publication of the Protein Society · 2021Article
- Mutant Ataxin-3-Containing Aggregates (MATAGGs) in Spinocerebellar Ataxia Type 3: Dynamics of the Disorder.Molecular neurobiology · 2021Review
- The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors.Journal of neuropathology and experimental neurology · 2021Review
- (Dis)Solving the problem of aberrant protein states.Disease models & mechanisms · 2021Review
- Combating deleterious phase transitions in neurodegenerative disease.Biochimica et biophysica acta. Molecular cell research · 2021Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
There are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ) disorders, including Spinocerebellar Ataxia Type-3 (SCA3). Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase from yeast, which is bafflingly absent from metazoa. Hsp104 suppressed eye degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, but unexpectedly enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 suppressed toxicity of MJD variants lacking a portion of the N-terminal deubiquitylase domain and full-length MJD variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 modalities. Importantly, in staging experiments, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.