ArticleProceedings of the National Academy of Sciences of the United States of America2014
Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 64 citations in OpenAlex.
- Nutrient and heat stress induce changes to the solubility of predicted prion-like proteins in Dictyostelium discoideum.BMC molecular and cell biology · 2026Article
- GFP-free live neuron quantitative imaging reveals compartmentalization and growth dynamics of polyQ aggregates.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures.Molecular systems biology · 2025Article
- Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin.Nature communications · 2025Article
- Intrinsically Disordered Compositional Bias in Proteins: Sequence Traits, Region Clustering, and Generation of Hypothetical Functional Associations.Bioinformatics and biology insights · 2024Article
- The yeast 14-3-3 proteins Bmh1 and Bmh2 regulate key signaling pathways.Frontiers in molecular biosciences · 2024Review
- ULK1 forms distinct oligomeric states and nanoscopic structures during autophagy initiation.Science advances · 2023Article
- Saccharomyces cerevisiae as a research tool for RNA-mediated human disease.Wiley interdisciplinary reviews. RNA · 2023Review
- Huntington's disease age at motor onset is modified by the tandem hexamer repeat in TCERG1.NPJ genomic medicine · 2022Article
- A rare natural lipid induces neuroglobin expression to prevent amyloid oligomers toxicity and retinal neurodegeneration.Aging cell · 2022Article
- Modifier pathways in polyglutamine (PolyQ) diseases: from genetic screens to drug targets.Cellular and molecular life sciences : CMLS · 2022Review
- Clearance of an amyloid-like translational repressor is governed by 14-3-3 proteins.Cell reports · 2022Article
- Dynamics of huntingtin protein interactions in the striatum identifies candidate modifiers of Huntington disease.Cell systems · 2022Article
- Mutant Huntingtin Protein Interaction Map Implicates Dysregulation of Multiple Cellular Pathways in Neurodegeneration of Huntington's Disease.Journal of Huntington's disease · 2022Article
- The engineered expression of secreted HSPB5-Fc in CHO cells exhibits cytoprotection in vitro.BMC biotechnology · 2021Article
- Sis1 potentiates the stress response to protein aggregation and elevated temperature.Nature communications · 2020Article
- A role of cellular translation regulation associated with toxic Huntingtin protein.Cellular and molecular life sciences : CMLS · 2020Article
- Connecting Coil-to-Globule Transitions to Full Phase Diagrams for Intrinsically Disordered Proteins.Biophysical journal · 2020Article
- Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau.Nature communications · 2020Article
- Application of yeast to studying amyloid and prion diseases.Advances in genetics · 2020Review
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
Expansion of a poly-glutamine (polyQ) repeat in a group of functionally unrelated proteins is the cause of several inherited neurodegenerative disorders, including Huntington's disease. The polyQ length-dependent aggregation and toxicity of these disease proteins can be reproduced in Saccharomyces cerevisiae. This system allowed us to screen for genes that when overexpressed reduce the toxic effects of an N-terminal fragment of mutant huntingtin with 103 Q. Surprisingly, among the identified suppressors were three proteins with Q-rich, prion-like domains (PrDs): glycine threonine serine repeat protein (Gts1p), nuclear polyadenylated RNA-binding protein 3, and minichromosome maintenance protein 1. Overexpression of the PrD of Gts1p, containing an imperfect 28 residue glutamine-alanine repeat, was sufficient for suppression of toxicity. Association with this discontinuous polyQ domain did not prevent 103Q aggregation, but altered the physical properties of the aggregates, most likely early in the assembly pathway, as reflected in their increased SDS solubility. Molecular simulations suggested that Gts1p arrests the aggregation of polyQ molecules at the level of nonfibrillar species, acting as a cap that destabilizes intermediates on path to form large fibrils. Quantitative proteomic analysis of polyQ interactors showed that expression of Gts1p reduced the interaction between polyQ and other prion-like proteins, and enhanced the association of molecular chaperones with the aggregates. These findings demonstrate that short, Q-rich peptides are able to shield the interactive surfaces of toxic forms of polyQ proteins and direct them into nontoxic aggregates.
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