The expansion of CAG repeats over time in certain cells, known as somatic instability, has garnered increasing attention in the HD field in recent years. Research efforts are underway across the globe to better understand this phenomenon, its underlying mechanisms, and how CAG expansion may drive HD symptoms.
Historical Context
Original evidence for somatic instability
Current scientific literature that explores CAG repeat expansion inevitably cites a 2003 paper by Peggy Shelbourne at the University of Glasgow. Nearly two decades before somatic instability began to gain prominence as a potential new therapeutic strategy for HD, her lab showed that CAG repeats were expanding in HD mouse brain tissue, and in the human striatum.
This paper measured widespread lengthening of CAG repeats in brain tissue, and occasionally repeats of up to 700, especially in the vulnerable striatum. The authors wrote that it was “tempting to speculate that the brain region-specific, expansion-biased size changes of the CAG repeat may play a role in progressive aspects of HD pathology and consequent symptomatology.”
It took nearly two decades for this theory to take hold, and scientific technology has improved such that researchers have more recently gathered much more direct evidence for the connection between CAG repeat expansion and HD symptoms.
Laura Kennedy, Elizabeth Evans, Chiung-Mei Chen, Lyndsey Craven, Peter J. Detloff, Margaret Ennis, Peggy F. Shelbourne, Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis, Human Molecular Genetics, Volume 12, Issue 24, 15 December 2003, Pages 3359–3367, https://doi.org/10.1093/hmg/ddg352
Learning from Young Adults
Evidence in humans connecting CAG expansion with HD brain atrophy
It has been particularly challenging to link somatic instability with neurodegeneration in living humans, because it occurs less prominently in accessible tissues like the blood.
A group led by Dr. Sarah Tabrizi of University College London recently provided evidence for this connection. They examined blood samples, brain images, and behavioral data from the HD Young Adult Study (HD-YAS) which involved participants who are ~23 years from predicted motor onset of HD. Gene-positive individuals who had no cognitive, behavioral, or motor signs of HD (ISS stage 0/1) nevertheless showed signs of brain atrophy and subtle white matter changes, as well as altered HD-relevant biomarkers (NfL and PENK).
Most notably, the authors were able to use highly sensitive methods for measuring CAG repeat expansion in blood samples. They found that participants who were expected to be two decades from HD onset showed increases in somatic expansion over the course of the study (4.5 years), with higher rates of expansion in people with higher CAGs. This study provides unprecedented evidence in humans that expanding CAGs could be driving brain atrophy in Huntington’s disease.
Scahill, R.I., Farag, M., Murphy, M.J. et al. Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington’s disease decades before clinical motor diagnosis. Nat Med (2025). https://doi.org/10.1038/s41591-024-03424-6
A Challenging Link
Evidence in brain tissue that CAG expansion drives neurodegeneration
A second groundbreaking study this year focused on the molecular aspects of somatic instability, examining post-mortem brain tissue from more than 100 people, many with known clinical information. This study helps to address the question of why the spiny projection neurons (SPNs) in the striatum are so vulnerable, leading to HD symptoms.
The laboratory of Steve McCarroll at Harvard/MIT developed a technique for measuring DNA and RNA changes at the single cell level. They can examine how expansions in CAG repeats are linked with changes in gene expression in different cell types.
They found that there is a CAG repeat expansion threshold (~150) at which spiny projection neurons begin to lose their identity and initiate molecular patterns that lead to their death. Before this threshold, the cells seem to be able to handle somatic instability. The authors suggest that therapeutic efforts focusing on reversing or halting the expansion of CAG repeats could potentially benefit pre-symptomatic and symptomatic individuals.
Handsaker RE, Kashin S, Reed NM, Tan S, Lee WS, McDonald TM, Morris K, Kamitaki N, Mullally CD, Morakabati NR, Goldman M, Lind G, Kohli R, Lawton E, Hogan M, Ichihara K, Berretta S, McCarroll SA. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease. Cell. 2025 Jan 14:S0092-8674(24)01379-5. doi: 10.1016/j.cell.2024.11.038. Epub ahead of print. PMID: 39824182.
