ArticleNeuron2022
Uninterrupted CAG repeat drives striatum-selective transcriptionopathy and nuclear pathogenesis in human Huntingtin BAC mice.
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Article in Neuron, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed.
- HDDF2-A Novel Patient-Derived Fibroblast Line from Huntington's Disease with Prominent Cellular Senescence and polyQ Pathology.Biomedicines · 2026Article
- Double strand breaks drive toxicity in a Huntington's disease mouse model with or without somatic expansion.Nature communications · 2026Article
- MBNL proteins in health, disease, and therapeutic applications.Nucleic acids research · 2026Review
- Repeat-associated non-AUG translation as a common mechanism for the polyGln ataxias.Cell reports · 2026Article
- Hydrogen Sulfide Signaling in Neurodegenerative Movement Disorders.Handbook of experimental pharmacology · 2026Review
- Molecular and imaging biomarker responses to brain mutant HTT lowering in a mouse model of Huntington disease.Molecular therapy. Nucleic acids · 2025Article
- Animal models of Huntington's disease. Pros and cons.Brain, behavior, & immunity - health · 2025Review
- A distal promoter and aberrant splicing enable canonical translation of out-of-frame proteins in Huntington's disease.bioRxiv : the preprint server for biology · 2025Article
- Double strand breaks drive toxicity in Huntington's disease mice with or without somatic expansion.bioRxiv : the preprint server for biology · 2025Article
- Epigenetic mechanisms governing cell type specific somatic expansion and toxicity in Huntington's disease.bioRxiv : the preprint server for biology · 2025Article
- Molecular Mechanisms of Spinocerebellar Ataxia Type 17.Molecular neurobiology · 2025Review
- Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures.Molecular systems biology · 2025Article
- Article
- Accelerated epigenetic aging in Huntington's disease involves polycomb repressive complex 1.Nature communications · 2025Article
- Absence of hippocampal pathology persists in the Q175DN mouse model of Huntington's disease despite elevated HTT aggregation.Journal of Huntington's disease · 2025Article
- Advances in Huntington's Disease Biomarkers: A 10-Year Bibliometric Analysis and a Comprehensive Review.Biology · 2025Review
- Insights into RNA-mediated pathology in new mouse models of Huntington's disease.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of CaMolecular therapy. Nucleic acids · 2024Article
- Therapeutic approaches targeting aging and cellular senescence in Huntington's disease.CNS neuroscience & therapeutics · 2024Review
- Huntington's disease cellular phenotypes are rescued non-cell autonomously by healthy cells in mosaic telencephalic organoids.Nature communications · 2024Article
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Authors and funding
21 authors.
Xiaofeng GuCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Jeffrey RichmanCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Peter LangfelderCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Nan WangCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Shasha ZhangCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Monica Bañez-CoronelCenter for Neurogenetics, Department of Molecular Genetics and Microbiology, College of Medicine, Genetics Institute, McKnight Brain Institute, Norman Fixel Institute of Neurological Diseases, University of Florida, Gainesville, FL, USA.
Huei-Bin WangDepartment Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Lucia YangCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Lalini RamanathanCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Linna DengCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Chang Sin ParkCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Christopher R ChoiCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Jeffrey P CantleCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Fuying GaoCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Michelle GrayDepartment of Neurology and Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA.
Giovanni CoppolaCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Gillian P BatesHuntington's Disease Centre, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Laura P W RanumCenter for Neurogenetics, Department of Molecular Genetics and Microbiology, College of Medicine, Genetics Institute, McKnight Brain Institute, Norman Fixel Institute of Neurological Diseases, University of Florida, Gainesville, FL, USA.
Steve HorvathDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Christopher S ColwellDepartment Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
X William YangCenter for Neurobehavioral Genetics, Jane and Terry Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: xwyang@mednet.ucla.edu.
Funding
UCLA IDDRC: Translational CoreP50HD103557 · NICHD · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI HARLEY IAN KORNBLUM · 2020 to 2026
$9.6MMolecular Genetic Characterization of SCA8R37NS040389 · NINDS · UNIVERSITY OF FLORIDA · PI RANUM, LAURA P.W · 2015 to 2021
$4.5MDendritome mapping of genetically-defined and sparsely-labeled cortical and striatal projection neuronsU01MH117079 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DONG, HONG-WEI, YANG, XIANGDONG WILLIAM · 2018 to 2022
$4.3MExploring the contribution of astrocytes to Huntington diseaseR01NS089750 · NINDS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI GRAY, MICHELLE · 2015 to 2024
$4.2MRepeat Associated non-AUG translation in Myotonic Dystrophy Type 1R01NS117910 · NINDS · UNIVERSITY OF FLORIDA · PI BANEZ-CORONEL, MONICA, RANUM, LAURA P.W · 2021 to 2025
$3.4MNovel mouse genetic models to study modifiers of Huntington’s diseaseR01NS113612 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI YANG, XIANGDONG WILLIAM · 2019 to 2023
$3.2MComplement-Microglia Interaction in Synaptic Loss and Neurodegeneration in HDR01NS084298 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI STEVENS, BETH ANN, YANG, XIANGDONG WILLIAM · 2014 to 2018
$1.8MThe Role of Astrocytes in Huntington's DiseaseK01NS069614 · NINDS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI GRAY, MICHELLE · 2010 to 2014
$874kNICHD NIH HHS P50 HD103557NIMH NIH HHS U01 MH117079NINDS NIH HHS K01 NS069614NINDS NIH HHS R01 NS084298NINDS NIH HHS R01 NS089750NINDS NIH HHS R01 NS113612NINDS NIH HHS R01 NS117910NINDS NIH HHS R37 NS040389
Abstract
In Huntington's disease (HD), the uninterrupted CAG repeat length, but not the polyglutamine length, predicts disease onset. However, the underlying pathobiology remains unclear. Here, we developed bacterial artificial chromosome (BAC) transgenic mice expressing human mutant huntingtin (mHTT) with uninterrupted, and somatically unstable, CAG repeats that exhibit progressive disease-related phenotypes. Unlike prior mHTT transgenic models with stable, CAA-interrupted, polyglutamine-encoding repeats, BAC-CAG mice show robust striatum-selective nuclear inclusions and transcriptional dysregulation resembling those in murine huntingtin knockin models and HD patients. Importantly, the striatal transcriptionopathy in HD models is significantly correlated with their uninterrupted CAG repeat length but not polyglutamine length. Finally, among the pathogenic entities originating from mHTT genomic transgenes and only present or enriched in the uninterrupted CAG repeat model, somatic CAG repeat instability and nuclear mHTT aggregation are best correlated with early-onset striatum-selective molecular pathogenesis and locomotor and sleep deficits, while repeat RNA-associated pathologies and repeat-associated non-AUG (RAN) translation may play less selective or late pathogenic roles, respectively.
Indexed as
Huntington DiseaseNerve Tissue ProteinsAnimalsChromosomes, Artificial, BacterialDisease Models, AnimalHumansHuntingtin ProteinMiceMice, TransgenicNeuronsNuclear ProteinsTrinucleotide Repeat ExpansionHuntingtin ProteinNerve Tissue ProteinsNuclear ProteinsaggregationBAC-CAGBACHDBAC transgenicCAG repeatHDHuntingtinHuntington’s diseaseinstabilityknockinmotor deficitsmuscleblindmutant huntingtinnuclear inclusionspolyglutamineRAN translationRNA fociRNA-seqstriatumtranscriptional dysregulationtranscriptionopathy
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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 Socratic graph.