ArticleHuman molecular genetics2015
Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington's disease.
Article in Human molecular genetics, 2015. 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.
- Development of aniScience · 2026Article
- Suppression of Huntington's Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding.Nature communications · 2025Article
- Post-Translational Modifications of Huntingtin: Mechanistic Insights and Therapeutic Opportunities in Huntington's Disease.International journal of molecular sciences · 2025Review
- GABAergic neuronal dysfunction underlies tremor in spinocerebellar ataxia 3.Disease models & mechanisms · 2025Article
- The dorsal fan-shaped body is a neurochemically heterogeneous sleep-regulating center in Drosophila.PLoS biology · 2025Article
- Exon 1-targeting miRNA reduces the pathogenic exon 1 HTT protein in Huntington's disease models.Brain : a journal of neurology · 2024Article
- Large animal models for Huntington's disease research.Zoological research · 2024Review
- The ubiquitin thioesterase YOD1 ameliorates mutant Huntingtin induced pathology in Drosophila.Scientific reports · 2023Article
- Article
- Dysregulated miRNA and mRNA Expression Affect Overlapping Pathways in a Huntington's Disease Model.International journal of molecular sciences · 2023Article
- Review
- Early detection of exon 1 huntingtin aggregation in zQ175 brains by molecular and histological approaches.Brain communications · 2023Article
- Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases.Frontiers in physiology · 2023Review
- Article
- Acetylation State of Lysine 14 of Histone H3.3 Affects Mutant Huntingtin Induced Pathogenesis.International journal of molecular sciences · 2022Article
- PAM-altering SNP-based allele-specific CRISPR-Cas9 therapeutic strategies for Huntington's disease.Molecular therapy. Methods & clinical development · 2022Article
- Gut Bacteria Regulate the Pathogenesis of Huntington's Disease inFrontiers in neuroscience · 2022Article
- Mutant Huntingtin Protein Interaction Map Implicates Dysregulation of Multiple Cellular Pathways in Neurodegeneration of Huntington's Disease.Journal of Huntington's disease · 2022Article
- Synaptic and functional alterations in the development of mutant huntingtin expressing hiPSC-derived neurons.Frontiers in molecular biosciences · 2022Article
- Emerging Therapies for Huntington's Disease - Focus on N-Terminal Huntingtin and Huntingtin Exon 1.Biologics : targets & therapy · 2022Review
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Although Huntington's disease is caused by the expansion of a CAG triplet repeat within the context of the 3144-amino acid huntingtin protein (HTT), studies reveal that N-terminal fragments of HTT containing the expanded PolyQ region can be produced by proteolytic processing and/or aberrant splicing. N-terminal HTT fragments are also prevalent in postmortem tissue, and expression of some of these fragments in model organisms can cause pathology. This has led to the hypothesis that N-terminal peptides may be critical modulators of disease pathology, raising the possibility that targeting aberrant splicing or proteolytic processing may present attractive therapeutic targets. However, many factors can contribute to pathology, including genetic background and differential expression of transgenes, in addition to intrinsic differences between fragments and their cellular effects. We have used Drosophila as a model system to determine the relative toxicities of different naturally occurring huntingtin fragments in a system in which genetic background, transgene expression levels and post-translational proteolytic processing can be controlled. These studies reveal that among the naturally occurring N-terminal HTT peptides, the exon 1 peptide is exceptionally pathogenic and exhibits unique structural and biophysical behaviors that do not appear to be incremental changes compared with other fragments. If this proves correct, efforts to specifically reduce the levels of exon 1 peptides or to target toxicity-influencing post-translational modifications that occur with the exon 1 context are likely to have the greatest impact on pathology.
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