ArticleBiochemistry2012
Kinetically competing huntingtin aggregation pathways control amyloid polymorphism and properties.
Article in Biochemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 88 citations in OpenAlex.
- Chaperone-mediated remodelling of mutant huntingtin.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Surface-modified protein crowders influence mutant huntingtin exon 1 aggregation via crowding effects, crowder association, and crowder solution stability.Protein science : a publication of the Protein Society · 2025Article
- Transient Interdomain Interactions Modulate the Monomeric Structural Ensemble and Self-Assembly of Huntingtin Exon 1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Direct Observation of Secondary Nucleation in Huntingtin Amyloid Formation by High-Speed Atomic Force Microscopy.Journal of the American Chemical Society · 2025Article
- Inhibitor-based modulation of huntingtin aggregation mechanisms mitigates fibril-induced cellular stress.Nature communications · 2025Article
- Solid-state nuclear magnetic resonance in the structural study of polyglutamine aggregation.Biochemical Society transactions · 2024Review
- Article
- Charge within Nt17 peptides modulates huntingtin aggregation and initial lipid binding events.Biophysical chemistry · 2023Article
- The structure of pathogenic huntingtin exon 1 defines the bases of its aggregation propensity.Nature structural & molecular biology · 2023Article
- Gene Alterations Induced by Glutamine (Q) Encoding CAG Repeats Associated with Neurodegeneration.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1.Communications biology · 2021Article
- An Expanded Polyproline Domain Maintains Mutant Huntingtin SolubleFrontiers in molecular neuroscience · 2021Article
- Amino acid homorepeats in proteins.Nature reviews. Chemistry · 2020Review
- Protofilament Structure and Supramolecular Polymorphism of Aggregated Mutant Huntingtin Exon 1.Journal of molecular biology · 2020Article
- Nucleation Inhibition of Huntingtin Protein (htt) by Polyproline PPII Helices: A Potential Interaction with the N-Terminal α-Helical Region of Htt.Biochemistry · 2020Article
- Investigating the interactions of the first 17 amino acid residues of Huntingtin with lipid vesicles using mass spectrometry and molecular dynamics.Journal of mass spectrometry : JMS · 2020Article
- Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington's disease.Experimental biology and medicine (Maywood, N.J.) · 2019Review
- The folding equilibrium of huntingtin exon 1 monomer depends on its polyglutamine tract.The Journal of biological chemistry · 2018Article
- Mutational analysis implicates the amyloid fibril as the toxic entity in Huntington's disease.Neurobiology of disease · 2018Article
- The 17-residue-long N terminus in huntingtin controls stepwise aggregation in solution and on membranes via different mechanisms.The Journal of biological chemistry · 2018Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
In polyglutamine (polyQ) containing fragments of the Huntington's disease protein huntingtin (htt), the N-terminal 17 amino acid htt(NT) segment serves as the core of α-helical oligomers whose reversible assembly locally concentrates the polyQ segments, thereby facilitating polyQ amyloid nucleation. A variety of aggregation inhibitors have been described that achieve their effects by neutralizing this concentrating function of the htt(NT) segment. In this paper we characterize the nature and limits of this inhibition for three means of suppressing htt(NT)-mediated aggregation. We show that the previously described action of htt(NT) peptide-based inhibitors is solely due to their ability to suppress the htt(NT)-mediated aggregation pathway. That is, under htt(NT) inhibition, nucleation of polyQ amyloid formation by a previously described alternative nucleation mechanism proceeds unabated and transiently dominates the aggregation process. Removal of the bulk of the htt(NT) segment by proteolysis or mutagenesis also blocks the htt(NT)-mediated pathway, allowing the alternative nucleation pathway to dominate. In contrast, the previously described immunoglobulin-based inhibitor, the antihtt(NT) V(L) 12.3 protein, effectively blocks both amyloid pathways, leading to stable accumulation of nonamyloid oligomers. These data show that the htt(NT)-dependent and -independent pathways of amyloid nucleation in polyQ-containing htt fragments are in direct kinetic competition. The results illustrate how amyloid polymorphism depends on assembly mechanism and kinetics and have implications for how the intracellular environment can influence aggregation pathways.
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