Huntington's cortical neuron loss linked to large somatic DNA repeat expansions

Overview

Updated 2 hours ago

Huntington's disease has long been framed as a protein problem: mutant huntingtin clumps inside neurons and kills them. A new Cell study maps 428,173 cortical cells and finds that the neurons most likely to die carry extreme somatic expansions of the CAG repeat, beyond 450 repeats.

The same map shows that the protein inclusions long blamed for toxicity cluster at intermediate expansions, 250 to 350 repeats, in cells with a distinct transcriptional profile. The two pathologies are not the same process.

Why it matters

If somatic expansion drives cortical cell loss, medicines that slow it could protect brain regions beyond the striatum.

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Key Indicators

428,173

Cortical cells imaged

Cells from control and Huntington's disease cortex mapped in intact tissue sections.

1,128

Genes measured per cell

MERFISH probes read gene expression alongside CAG repeat length and pathology markers.

>50%

Loss of vulnerable cortical neurons

Layer 5-6 near-projecting and L6b deep-layer excitatory neurons are depleted in disease.

>450

CAG repeats linked to cell loss

The most depleted neurons carry somatic expansions beyond 450 repeats, with about 55 repeats of measurement uncertainty.

Voices

Curated perspectives — historical figures and your fellow readers.

People Involved

Don W. Cleveland

Professor, University of California, San Diego; senior author

Active researcher

Sonia Vazquez-Sanchez

Researcher, University of California, San Diego; first author

Active researcher

Bogdan Bintu

Assistant professor, University of California, San Diego; co-author

Active researcher

Steve McCarroll

Geneticist, Broad Institute and Harvard Medical School; senior author of companion paper

Active researcher

Seva Kashin

Scientist, McCarroll lab, Broad Institute; co-first author

Active researcher

Organizations Involved

University of California San Diego

Public research university

Home institution of the cortical atlas authors

Public research university in La Jolla, California. Its labs produced the cortical atlas and the spatial imaging tools behind it.

Broad Institute of MIT and Harvard

Research institute

Produced companion paper and 2025 striatum study

Cambridge, Massachusetts research institute jointly run by MIT and Harvard. McCarroll's lab produced the companion paper and the 2025 striatum study.

Harvard Medical School

Medical school

Affiliation of McCarroll and Berretta

Medical school in Boston. McCarroll and Sabina Berretta hold appointments.

McLean Hospital

Psychiatric hospital

Affiliation of co-senior author Sabina Berretta

Psychiatric hospital in Belmont, Massachusetts, affiliated with Harvard. Sabina Berretta is a co-senior author.

Timeline

2025 October 2026

4 events Latest: 5 days ago

Tap a bar to jump to that date

October 2026
Cell publishes cortical spatial atlas
Latest Research

Cell publishes cortical atlas linking L5-6 NP and L6b loss to >450 repeats.
5 days ago
Companion paper maps striatal and cortical neurons
Research

Companion paper maps the same mechanism in striatal and cortical neurons.
5 days ago
Broad Institute frames cross-region mechanism
Statement

Broad Institute press release frames somatic expansion as cross-region driver.
5 days ago
2025
Striatum study links somatic expansion to toxicity
Research

McCarroll lab reports striatal cells turn toxic after 150+ CAG repeats.
2025

Scenarios

Somatic-expansion therapy enters human trials

Possible Resolves by End of 2028

Discussed by: Huntington's disease researchers and drug developers, including teams cited in the Broad Institute release.

A therapy designed to slow somatic CAG expansion, such as an MSH3 inhibitor or a DNA-repair-targeting drug, advances to a Phase 1 trial. The cortical atlas strengthens the case because it shows the mechanism operates in more than one brain region.

Independent labs confirm the >450-repeat threshold

Likely Resolves by End of 2027

Discussed by: The study authors and independent Huntington's disease geneticists.

A separate research group maps cortical tissue from a different donor cohort and reports the same association between large somatic expansions and loss of L5-6 NP and L6b neurons. Replication would turn a single atlas into a general rule.

A somatic-expansion drug fails to slow cortical loss

Unlikely Resolves by End of 2030

Discussed by: Clinical trial sponsors and independent reviewers.

A completed trial of a somatic-expansion therapy reports no measurable effect on cortical neuron loss or cognitive decline. That result would not necessarily disprove the mechanism, but it would separate a valid pathological finding from a workable drug target.

Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

1993

Huntington's disease gene discovery (1993)

A collaborative research group cloned the HTT gene and found that a CAG repeat expansion causes Huntington's disease. The discovery gave families a diagnostic test but did not explain why some brain regions degenerate faster than others.

Then

Genetic testing became possible; the protein product, huntingtin, became the focus of drug development.

Now

Decades of work targeted mutant huntingtin protein, with limited clinical success.

Why this matters now

The new study shifts attention from the protein to the DNA repeat itself.

2015-2019

DNA repair genes linked to HD onset (2015-2019)

Genome-wide association studies found that variants in DNA repair genes, including MSH3 and FAN1, modify the age at which Huntington's symptoms begin. The result pointed to somatic repeat expansion, not just the inherited repeat length.

Then

Researchers began measuring CAG repeat length in individual brain cells.

Now

Somatic expansion became a leading therapeutic target.

Why this matters now

The new cortical atlas measures those expansions cell by cell.

2025

Somatic expansion shown to drive striatal toxicity (2025)

A team led by Steve McCarroll reported that striatal neurons become toxic only after their CAG repeat expands beyond about 150 repeats. The finding reframed Huntington's as a DNA-level disease that progresses over decades.

Then

The result renewed interest in drugs that slow repeat expansion.

Now

It set up the question the new study answers: does the same mechanism operate in the cortex?

Why this matters now

The cortical study extends the mechanism to a second brain region.