ArticleProceedings of the National Academy of Sciences of the United States of America2017
Aggregation landscapes of Huntingtin exon 1 protein fragments and the critical repeat length for the onset of Huntington's disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. 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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46 citing papers in PubMed, 95 citations in OpenAlex.
- Lipid Composition Drives Mutant Huntingtin Dimerization and Membrane Association: Insights from Computational Simulations.Molecules (Basel, Switzerland) · 2026Article
- Real-time imaging of protein microenvironment changes in cells with rotor-based fluorescent amino acids.Nature chemical biology · 2026Article
- In situ secondary structure imaging of protein phase separation and aggregation by hyperspectral stimulated Raman scattering microscopy.Nature communications · 2025Article
- Huntington's chorea: emerging fields in therapeutics (Review).Neurogenetics · 2025Review
- Transient Interdomain Interactions Modulate the Monomeric Structural Ensemble and Self-Assembly of Huntingtin Exon 1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Generating the polymorph landscapes of amyloid fibrils using AI: RibbonFold.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Glutamine missense suppressor transfer RNAs inhibit polyglutamine aggregation.Molecular therapy. Nucleic acids · 2025Article
- Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease.Neurobiology of disease · 2025Article
- Long noncoding RNAs in ubiquitination, protein degradation, and human diseases.Biochimica et biophysica acta. Gene regulatory mechanisms · 2024Review
- Emerging roles of cannabinoid receptor CB2 receptor in the central nervous system: therapeutic target for CNS disorders.Psychopharmacology · 2024Review
- A perspective on age-related changes in cell environment and risk of neurodegenerative diseases.Neural regeneration research · 2024Article
- From Milliseconds to Minutes: Melittin Self-Assembly from Concerted Non-Equilibrium Pressure-Jump and Equilibrium Relaxation Nuclear Magnetic Resonance.The journal of physical chemistry letters · 2024Article
- The elementary reactions for incorporation into crystals.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- MicroRNA biomarkers as next-generation diagnostic tools for neurodegenerative diseases: a comprehensive review.Frontiers in molecular neuroscience · 2024Review
- A method for the analysis of the oligomerization profile of the Huntington's disease-associated, aggregation-prone mutant huntingtin protein by isopycnic ultracentrifugation.Frontiers in molecular biosciences · 2024Article
- Article
- Interaction between huntingtin exon 1 and HEAT repeat structure probed by chimeric model proteins.Protein science : a publication of the Protein Society · 2023Article
- From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington's Disease Research.International journal of molecular sciences · 2023Review
- Role of conformational dynamics in pathogenic protein aggregation.Current opinion in chemical biology · 2023Review
- Cannabinoid CB2 Receptors in Neurodegenerative Proteinopathies: New Insights and Therapeutic Potential.Biomedicines · 2022Review
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2 authors at 1 institution in 1 country.
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Abstract
Huntington's disease (HD) is a neurodegenerative disease caused by an abnormal expansion in the polyglutamine (polyQ) track of the Huntingtin (HTT) protein. The severity of the disease depends on the polyQ repeat length, arising only in patients with proteins having 36 repeats or more. Previous studies have shown that the aggregation of N-terminal fragments (encoded by HTT exon 1) underlies the disease pathology in mouse models and that the HTT exon 1 gene product can self-assemble into amyloid structures. Here, we provide detailed structural mechanisms for aggregation of several protein fragments encoded by HTT exon 1 by using the associative memory, water-mediated, structure and energy model (AWSEM) to construct their free energy landscapes. We find that the addition of the N-terminal 17-residue sequence ([Formula: see text]) facilitates polyQ aggregation by encouraging the formation of prefibrillar oligomers, whereas adding the C-terminal polyproline sequence ([Formula: see text]) inhibits aggregation. The combination of both terminal additions in HTT exon 1 fragment leads to a complex aggregation mechanism with a basic core that resembles that found for the aggregation of pure polyQ repeats using AWSEM. At the extrapolated physiological concentration, although the grand canonical free energy profiles are uphill for HTT exon 1 fragments having 20 or 30 glutamines, the aggregation landscape for fragments with 40 repeats has become downhill. This computational prediction agrees with the critical length found for the onset of HD and suggests potential therapies based on blocking early binding events involving the terminal additions to the polyQ repeats.
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