ArticleNeurobiology of disease2018
Mutational analysis implicates the amyloid fibril as the toxic entity in Huntington's disease.
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 20 papers.
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Who cites it
20 citing papers in PubMed.
- Short CAG repeat variation as a regulatory factor in health and disease.Frontiers in genetics · 2026Review
- Direct Observation of Secondary Nucleation in Huntingtin Amyloid Formation by High-Speed Atomic Force Microscopy.Journal of the American Chemical Society · 2025Article
- Glutamine missense suppressor transfer RNAs inhibit polyglutamine aggregation.Molecular therapy. Nucleic acids · 2025Article
- Article
- Non-fibril form but not fibril form of human islet amyloid polypeptide 8-20 changes brain functions in mice.PloS one · 2024Article
- The structure of pathogenic huntingtin exon 1 defines the bases of its aggregation propensity.Nature structural & molecular biology · 2023Article
- Oxidation Promotes Distinct Huntingtin Aggregates in the Presence and Absence of Membranes.Biochemistry · 2022Article
- Toxicity of internalized polyalanine to cells depends on aggregation.Scientific reports · 2021Article
- Mitochondrial membranes modify mutant huntingtin aggregation.Biochimica et biophysica acta. Biomembranes · 2021Article
- Macromolecular crowding in solution alters huntingtin interaction and aggregation at interfaces.Colloids and surfaces. B, Biointerfaces · 2021Article
- Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates.Scientific reports · 2021Article
- Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington's disease.Acta neuropathologica communications · 2021Article
- Molecular Strategies to Target Protein Aggregation in Huntington's Disease.Frontiers in molecular biosciences · 2021Review
- An Expanded Polyproline Domain Maintains Mutant Huntingtin SolubleFrontiers in molecular neuroscience · 2021Article
- Lipid headgroups alter huntingtin aggregation on membranes.Biochimica et biophysica acta. Biomembranes · 2021Article
- Implications of the Orb2 Amyloid Structure in Huntington's Disease.International journal of molecular sciences · 2020Review
- Protofilament Structure and Supramolecular Polymorphism of Aggregated Mutant Huntingtin Exon 1.Journal of molecular biology · 2020Article
- How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington's Disease? A Comprehensive Review.International journal of molecular sciences · 2020Review
- Million-fold sensitivity enhancement in proteopathic seed amplification assays for biospecimens by Hofmeister ion comparisons.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Yeast Models for the Study of Amyloid-Associated Disorders and Development of Future Therapy.Frontiers in molecular biosciences · 2019Review
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Authors and funding
6 authors.
Funding
Abstract
In Huntington disease (HD), an expanded polyglutamine (polyQ > 37) sequence within huntingtin (htt) exon1 leads to enhanced disease risk. It has proved difficult, however, to determine whether the toxic form generated by polyQ expansion is a misfolded or avid-binding monomer, an α-helix-rich oligomer, or a β-sheet-rich amyloid fibril. Here we describe an engineered htt exon1 analog featuring a short polyQ sequence that nonetheless quickly forms amyloid fibrils and causes HD-like toxicity in rat neurons and Drosophila. Additional modifications within the polyQ segment produce htt exon1 analogs that populate only spherical oligomers and are non-toxic in cells and flies. Furthermore, in mixture with expanded-polyQ htt exon1, the latter analogs in vitro suppress amyloid formation and promote oligomer formation, and in vivo rescue neurons and flies expressing mhtt exon1 from dysfunction and death. Thus, in our experiments, while htt exon1 toxicity tracks with aggregation propensity, it does so in spite of the toxic construct's possessing polyQ tracts well below those normally considered to be disease-associated. That is, aggregation propensity proves to be a more accurate surrogate for toxicity than is polyQ repeat length itself, strongly supporting a major toxic role for htt exon1 aggregation in HD. In addition, the results suggest that the aggregates that are most toxic in these model systems are amyloid-related. These engineered analogs are novel tools for mapping properties of polyQ self-assembly intermediates and products that should similarly be useful in the analysis of other expanded polyQ diseases. Small molecules with similar amyloid inhibitory properties might be developed into effective therapeutic agents.
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