Evidence map›Paper›PMID 39938516›Full record

ArticleCell2025

Distinct mismatch-repair complex genes set neuronal CAG-repeat expansion rate to drive selective pathogenesis in HD mice.

Nan Wang, Shasha Zhang, Peter Langfelder, Lalini Ramanathan, Fuying Gao, Mary Plascencia, Raymond Vaca, Xiaofeng Gu, Linna Deng, Leonardo E Dionisio and 9 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.

0numbers the graph read from it
0cells of the map it votes in
30citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

30 citing papers in PubMed.

  1. Article
  2. Towards AI-driven prediction ofJournal of Huntington's disease · 2026
    Article
  3. Article
  4. Article
  5. Review
  6. Article
  7. Article
  8. Article
  9. Decoding neurodegeneration one cell at a time.The Journal of clinical investigation · 2026
    Review
  10. Article
  11. Article
  12. Huntington's disease clinical trials update: October 2025.Journal of Huntington's disease · 2026
    Review
  13. Article
  14. Review
  15. Article
  16. Review
  17. Article
  18. Article
  19. Article
  20. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

19 authors.

Nan WangCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Shasha ZhangCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Peter LangfelderCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Lalini RamanathanCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Fuying GaoCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Mary PlascenciaCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Raymond VacaCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Xiaofeng GuCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Linna DengCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Leonardo E DionisioCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Ha VuDepartment of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
Emily MaciejewskiDepartment of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
Jason ErnstDepartment of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
Brinda C PrasadCHDI Management, Inc., Princeton, NJ, USA.
Thomas F VogtCHDI Management, Inc., Princeton, NJ, USA.
Steve HorvathDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Altos Labs, Cambridge, UK.
Jeffrey S AaronsonCHDI Management, Inc., Princeton, NJ, USA.
Jim RosinskiCHDI Management, Inc., Princeton, NJ, USA.
X William YangCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: xwyang@mednet.ucla.edu.

Funding

Training Grant in Genomic Analysis and InterpretationT32HG002536 · NHGRI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Valerie A Arboleda, Harold Pimentel · 2002 to 2026
$8.6M
Novel mouse genetic models to study modifiers of Huntington’s diseaseR01NS113612 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI YANG, XIANGDONG WILLIAM · 2019 to 2023
$3.2M
NHGRI NIH HHS T32 HG002536NINDS NIH HHS R01 NS113612
6 · The paper itself

Abstract

Huntington's disease (HD) modifiers include mismatch-repair (MMR) genes, but their connections to neuronal pathogenesis remain unclear. Here, we genetically tested 9 HD genome-wide association study (GWAS)/MMR genes in mutant Huntingtin (mHtt) mice with 140 inherited CAG repeats (Q140). Knockout (KO) of genes encoding a distinct MMR complex either strongly (Msh3 and Pms1) or moderately (Msh2 and Mlh1) rescues phenotypes with early onset in striatal medium-spiny neurons (MSNs) and late onset in the cortical neurons: somatic CAG-repeat expansion, transcriptionopathy, and mHtt aggregation. Msh3 deficiency ameliorates open-chromatin dysregulation in Q140 neurons. Mechanistically, the fast linear rate of mHtt modal-CAG-repeat expansion in MSNs (8.8 repeats/month) is drastically reduced or stopped by MMR mutants. Msh3 or Pms1 deficiency prevents mHtt aggregation by keeping somatic MSN CAG length below 150. Importantly, Msh3 deficiency corrects synaptic, astrocytic, and locomotor defects in HD mice. Thus, Msh3 and Pms1 drive fast somatic mHtt CAG-expansion rates in HD-vulnerable neurons to elicit repeat-length/threshold-dependent, selective, and progressive pathogenesis in vivo.

Indexed as

DNA Mismatch RepairHuntington DiseaseNeuronsTrinucleotide Repeat ExpansionAnimalsDisease Models, AnimalDNA-Binding ProteinsGenome-Wide Association StudyHumansHuntingtin ProteinMaleMiceMice, KnockoutMutL Protein Homolog 1MutS Homolog 2 ProteinMutS Homolog 3 ProteinDNA-Binding ProteinsHuntingtin ProteinMlh1 protein, mouseMsh2 protein, mouseMsh3 protein, mouseMutL Protein Homolog 1MutS Homolog 2 ProteinMutS Homolog 3 ProteinaggregateATAC-seqCAG repeatchromatincortexHuntingtinHuntington's diseasemismatch repairMlh1Msh2Msh3neuronsPms1raterepeat expansionrepeat instabilityRNA-seqselective vulnerabilitystriatumthreshold

Identifiers

PMID39938516
PMCPMC11972609

What OpenQuestion holds

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Registered trials

None linked

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.