LARGE genetic expansions within vulnerable brain cells may contribute to neuronal loss and disease progression in Huntington’s disease (HD), according to new research.
The findings provide evidence that somatic expansion of the HTT CAG repeat accumulates specifically within medium spiny neurons (MSNs), the striatal neurons progressively lost in HD. Researchers also identified substantially greater expansion and neuronal loss among individuals carrying a genetic variant known to accelerate disease onset. Large CAG expansions accumulated in vulnerable brain cells and were associated with neuronal loss in Huntington’s disease.
Investigating CAG Expansion in the Human Brain
HD is caused by an expanded CAG repeat within the HTT gene, with inherited repeat length strongly influencing when symptoms develop. However, CAG repeats can continue expanding within individual cells throughout life, known as somatic expansion.
To investigate whether these changes contribute directly to HD pathology, researchers analysed blood and postmortem brain tissue from individuals with HD, including carriers of the CAG-CCG loss-of-interruption (LOI) variant.
This genetic modifier can accelerate HD onset by more than a decade, making it particularly useful for investigating the relationship between CAG expansion and neuronal degeneration.
The researchers examined several brain regions and isolated MSNs from the caudate, enabling CAG repeat lengths to be assessed specifically within a neuronal population particularly vulnerable to HD.
Large Expansions Accumulate in Vulnerable Neurons
Large CAG expansions were uncommon during early HD but accumulated as disease duration increased.
Among individuals with the conventional HTT sequence, large expansions of 111–150 CAG repeats were detected in 3.4% of caudate MSNs 1 year after motor onset, compared with 10.7% after 15 years. Very large expansions exceeding 150 repeats increased from 0.8% to 16.1% over the same period.
The effect was substantially greater among carriers of the CAG-CCG LOI variant.
At 1 year following motor onset, very large expansions were identified in 26.0% of MSNs from an LOI carrier compared with 0.8% in a matched individual with the conventional sequence. Across matched disease durations, large and very large expansions were approximately five times more frequent among LOI carriers.
By 10 years after motor onset, 58.9% of caudate MSNs in an LOI carrier contained expansions exceeding 150 CAG repeats.
Blood May Not Reflect Changes in the Brain
Importantly, the researchers found that blood measurements did not reflect these disease-relevant changes.
Despite dramatically increased expansion within MSNs, individuals carrying the LOI variant showed reduced small somatic expansions in blood. This suggests that peripheral blood may be a poor biomarker for assessing CAG expansion occurring within vulnerable neurons.
LOI carriers also had significantly fewer MSNs in the caudate, supporting an association between increased somatic expansion and accelerated neuronal loss.
The findings challenge the idea that crossing a single CAG threshold immediately causes neuronal death. MSNs containing more than 150 repeats remained detectable in the brains of individuals with longstanding disease, suggesting that extreme expansion may increase neuronal vulnerability rather than inevitably triggering immediate cell death.
The researchers conclude that cell-specific somatic HTT CAG expansion may be an important driver of HD pathology and highlight the need to investigate genetic changes directly within the neuronal populations affected by repeat expansion disorders.
Reference
Kay C et al. Loss of interruption in the HTT CAG repeat is associated with somatic expansion and loss of medium spiny neurons in Huntington’s disease. Neuron. 2026.
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