ArticleCell death and differentiation2022
The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities.
Article in Cell death and differentiation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 34 citations in OpenAlex.
- Discovery of a mutation-containing circRNA in polyglutamine disease through systematic analysis of RNAs with CAG repeats.RNA biology · 2026Article
- Human-specific sequence features in HTT exon 1 promote toxic misprocessing via splicing factor SRSF7.Nature communications · 2026Article
- Observational
- Short CAG repeat variation as a regulatory factor in health and disease.Frontiers in genetics · 2026Review
- Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.Autophagy · 2026Review
- Buried Treasure? Overlooked and Newly Discovered Evolutionary Contributions to Human Brain Diseases.Annals of neurology · 2025Review
- Childhood to Adult Neurodevelopment in Gene-Expanded Huntington's Disease (ChANGE-HD) study protocol: A Prospective Longitudinal Neurodevelopmental Study of Huntington's Disease.medRxiv : the preprint server for health sciences · 2025Article
- Effects of exercise on neuroinflammation in age-related neurodegenerative disorders.European journal of medical research · 2025Review
- Revolutionizing Huntington's Disease Treatment: Breakthroughs in AAV-Mediated Gene Therapy.Cells · 2025Review
- The evolution of eukaryotic linear motifs governing the function of androgen receptor from fish to Homo sapiens.Nucleic acids research · 2025Article
- When repetita no-longer iuvant: somatic instability of the CAG triplet in Huntington's disease.Nucleic acids research · 2025Review
- Navigating triplet repeats sequencing: concepts, methodological challenges and perspective for Huntington's disease.Nucleic acids research · 2025Review
- Short tandem repeat variants are possibly associated with RNA secondary structure and gene expression.PloS one · 2025Article
- C-reactive protein: the nexus between inflammation and protein misfolding diseases.Frontiers in immunology · 2025Review
- The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Evolutionary model of repeat insertions in Ataxin-3 traces the origin of the polyglutamine stretch to an ancestral ubiquitin binding module.Protein science : a publication of the Protein Society · 2024Article
- Mutant Huntingtin Drives Development of an Advantageous Brain Early in Life: Evidence in Support of Antagonistic Pleiotropy.Annals of neurology · 2024Article
- Article
- Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration.ACS chemical neuroscience · 2024Review
- Therapeutic and diagnostic applications of antisense peptide nucleic acids.Molecular therapy. Nucleic acids · 2024Review
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Authors and funding
19 authors at 6 institutions in 4 countries.
Funding
Abstract
Huntington's disease is caused by a pathologically long (>35) CAG repeat located in the first exon of the Huntingtin gene (HTT). While pathologically expanded CAG repeats are the focus of extensive investigations, non-pathogenic CAG tracts in protein-coding genes are less well characterized. Here, we investigated the function and evolution of the physiological CAG tract in the HTT gene. We show that the poly-glutamine (polyQ) tract encoded by CAGs in the huntingtin protein (HTT) is under purifying selection and subjected to stronger selective pressures than CAG-encoded polyQ tracts in other proteins. For natural selection to operate, the polyQ must perform a function. By combining genome-edited mouse embryonic stem cells and cell assays, we show that small variations in HTT polyQ lengths significantly correlate with cells' neurogenic potential and with changes in the gene transcription network governing neuronal function. We conclude that during evolution natural selection promotes the conservation and purity of the CAG-encoded polyQ tract and that small increases in its physiological length influence neural functions of HTT. We propose that these changes in HTT polyQ length contribute to evolutionary fitness including potentially to the development of a more complex nervous system.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.