Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease

Robert E Handsaker¹, Seva Kashin², Nora M Reed³, Steven Tan³, Won-Seok Lee³, Tara M McDonald³, Kiely Morris⁴, Nolan Kamitaki³, Christopher D Mullally³, Neda R Morakabati⁴, Melissa Goldman³, Gabriel Lind³, Rhea Kohli³, Elisabeth Lawton⁴, Marina Hogan³, Kiku Ichihara³, Sabina Berretta⁵, Steven A McCarroll⁶

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: handsake@broadinstitute.org.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: skashin@broadinstitute.org.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁴ McLean Hospital, Belmont, MA 02478, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02215, USA. Electronic address: sberretta@mclean.harvard.edu.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Boston, MA 02215, USA. Electronic address: smccarro@broadinstitute.org.

PMID: 39824182
PMCID: PMC11822645 (available on 2026-02-06)
DOI: 10.1016/j.cell.2024.11.038

Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease

Robert E Handsaker et al. Cell. 2025.

. 2025 Feb 6;188(3):623-639.e19.

doi: 10.1016/j.cell.2024.11.038. Epub 2025 Jan 16.

Authors

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: handsake@broadinstitute.org.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: skashin@broadinstitute.org.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁴ McLean Hospital, Belmont, MA 02478, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02215, USA. Electronic address: sberretta@mclean.harvard.edu.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Boston, MA 02215, USA. Electronic address: smccarro@broadinstitute.org.

PMID: 39824182
PMCID: PMC11822645 (available on 2026-02-06)
DOI: 10.1016/j.cell.2024.11.038

Abstract

In Huntington's disease (HD), striatal projection neurons (SPNs) degenerate during midlife; the core biological question involves how the disease-causing DNA repeat (CAG)_n in the huntingtin (HTT) gene leads to neurodegeneration after decades of biological latency. We developed a single-cell method for measuring this repeat's length alongside genome-wide RNA expression. We found that the HTT CAG repeat expands somatically from 40-45 to 100-500+ CAGs in SPNs. Somatic expansion from 40 to 150 CAGs had no apparent cell-autonomous effect, but SPNs with 150-500+ CAGs lost positive and then negative features of neuronal identity, de-repressed senescence/apoptosis genes, and were lost. Our results suggest that somatic repeat expansion beyond 150 CAGs causes SPNs to degenerate quickly and asynchronously. We conclude that in HD, at any one time, most neurons have an innocuous but unstable HTT gene and that HD pathogenesis is a DNA process for almost all of a neuron's life.

Keywords: CAG; DNA repeats; Huntington’s disease; neurodegeneration; repeat instability; single-nucleus RNA-seq; somatic expansion; striatal projection neurons; triplet repeat disorders.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests Patent applications filed by the Broad Institute of MIT and Harvard related to this work include subsets of the authors as inventors. S.A.M. has received compensation for scientific advice to Roche, Pfizer, Biogen, Vertex, and LoQus23 Therapeutics.

References

1. Huntington’s Disease Collaborative Research Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983. - PubMed
1. Gusella JF, Lee J-M, and MacDonald ME (2021). Huntington’s disease: nearly four decades of human molecular genetics. Hum. Mol. Genet. 30, R254–R263. - PMC - PubMed
1. Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR, and International Huntington’s Disease Collaborative Group (2004). A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin. Genet. 65, 267–277. - PubMed
1. Scahill RI, Zeun P, Osborne-Crowley K, Johnson EB, Gregory S, Parker C, Lowe J, Nair A, O’Callaghan C, Langley C, et al. (2020). Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington’s disease Young Adult Study (HD-YAS): a cross-sectional analysis. Lancet Neurol. 19, 502–512. - PMC - PubMed
1. Tabrizi SJ, Schobel S, Gantman EC, Mansbach A, Borowsky B, Konstantinova P, Mestre TA, Panagoulias J, Ross CA, Zauderer M, et al. (2022). A biological classification of Huntington’s disease: the Integrated Staging System. Lancet Neurol. 21, 632–644. - PubMed

MeSH terms

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

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

Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease

Affiliations

Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical