. 2025 Mar 20;188(6):1524-1544.e22.

doi: 10.1016/j.cell.2025.01.031. Epub 2025 Feb 11.

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

Nan Wang¹, Shasha Zhang¹, Peter Langfelder¹, Lalini Ramanathan¹, Fuying Gao¹, Mary Plascencia¹, Raymond Vaca¹, Xiaofeng Gu¹, Linna Deng¹, Leonardo E Dionisio¹, Ha Vu², Emily Maciejewski², Jason Ernst², Brinda C Prasad³, Thomas F Vogt³, Steve Horvath⁴, Jeffrey S Aaronson³, Jim Rosinski³, X William Yang⁵

Affiliations

¹ Center 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.
² Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
³ CHDI Management, Inc., Princeton, NJ, USA.
⁴ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Altos Labs, Cambridge, UK.
⁵ Center 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.

PMID: 39938516
PMCID: PMC11972609 (available on 2026-03-20)
DOI: 10.1016/j.cell.2025.01.031

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

Nan Wang et al. Cell. 2025.

. 2025 Mar 20;188(6):1524-1544.e22.

doi: 10.1016/j.cell.2025.01.031. Epub 2025 Feb 11.

Authors

Affiliations

¹ Center 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.
² Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
³ CHDI Management, Inc., Princeton, NJ, USA.
⁴ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Altos Labs, Cambridge, UK.
⁵ Center 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.

PMID: 39938516
PMCID: PMC11972609 (available on 2026-03-20)
DOI: 10.1016/j.cell.2025.01.031

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.

Keywords: ATAC-seq; CAG repeat; Huntingtin; Huntington's disease; Mlh1; Msh2; Msh3; Pms1; RNA-seq; aggregate; chromatin; cortex; mismatch repair; neurons; rate; repeat expansion; repeat instability; selective vulnerability; striatum; threshold.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests X.W.Y. is a Scientific Advisory Board member for Lyterian and Ophidion and a consultant/seminar speaker for Ionis, Biogen, Novartis, Roche, LifeEdit, PTC, Ascidian, Sangamo, and Forbion. P.L. served as an occasional consultant for The Bioinformatics CRO, Vynance, and FOXO Technologies, Inc. S.H. works for Altos Labs, UK.

Update of

Msh3 and Pms1 Set Neuronal CAG-repeat Migration Rate to Drive Selective Striatal and Cortical Pathogenesis in HD Mice.
Wang N, Zhang S, Langfelder P, Ramanathan L, Plascencia M, Gao F, Vaca R, Gu X, Deng L, Dionisio LE, Prasad BC, Vogt T, Horvath S, Aaronson JS, Rosinski J, Yang XW. Wang N, et al. bioRxiv [Preprint]. 2024 Jul 15:2024.07.09.602815. doi: 10.1101/2024.07.09.602815. bioRxiv. 2024. Update in: Cell. 2025 Mar 20;188(6):1524-1544.e22. doi: 10.1016/j.cell.2025.01.031. PMID: 39026894 Free PMC article. Updated. Preprint.

References

1. Ross CA, Aylward EH, Wild EJ, Langbehn DR, Long JD, Warner JH, Scahill RI, Leavitt BR, Stout JC, Paulsen JS, et al. (2014). Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 10, 204–216. 10.1038/nrneurol.2014.24. - DOI - PubMed
1. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. (1993). Cell 72, 971–983. 10.1016/0092-8674(93)90585-e. - DOI - PubMed
1. Vonsattel JP, and DiFiglia M (1998). Huntington disease. Journal of neuropathology and experimental neurology 57, 369–384. - PubMed
1. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, and Aronin N (1997). Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993. 10.1126/science.277.5334.1990. - DOI - PubMed
1. Arrasate M, and Finkbeiner S (2012). Protein aggregates in Huntington’s disease. Exp Neurol 238, 1–11. 10.1016/j.expneurol.2011.12.013. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

R01 NS113612/NS/NINDS NIH HHS/United States

LinkOut - more resources

Full Text Sources
- Elsevier Science
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials

Miscellaneous