Researchers at the Broad Institute of MIT and Harvard, Harvard Medical School, and McLean Hospital have made a groundbreaking discovery in the understanding of Huntington’s disease, a devastating neurodegenerative disorder. For over 30 years, scientists have known that Huntington’s is caused by a mutation in the HTT gene, but the exact mechanisms through which this mutation leads to the death of brain cells remained unclear. A new study, published in Cell, reveals a surprising mechanism by which the inherited mutation that causes Huntington’s disease slowly leads to the degeneration of brain cells, offering new insights into potential ways to delay or even prevent the disease.
What We Know About Huntington’s Disease
Huntington’s disease is a genetic disorder that causes the progressive breakdown of nerve cells in the brain. It is inherited in an autosomal dominant manner, meaning an individual with one affected parent has a 50% chance of inheriting the disease. The disorder primarily affects cells in the brain’s striatum, which is involved in controlling movement, cognition, and motivation.
The disease is caused by an abnormal expansion of a CAG repeat in the HTT gene. In a healthy individual, the HTT gene contains a region where the DNA sequence “CAG” repeats between 15 and 35 times. However, in individuals with Huntington’s disease, the number of repeats exceeds 40, with the number of repeats typically correlating with the severity of the disease. The longer the CAG expansion, the earlier the symptoms tend to appear. Symptoms usually begin in mid-adulthood and progressively worsen over the following decades, leading to movement difficulties, cognitive impairments, and psychiatric symptoms.
A Surprising Discovery: How the Mutation Leads to Brain Cell Death
For decades, scientists knew that Huntington’s disease was caused by the expansion of CAG repeats, but they did not understand how this genetic mutation led to the death of brain cells. This new research, led by Steve McCarroll and his colleagues, reveals a previously unknown mechanism that could explain the disease’s progression.
Rather than the inherited CAG mutation being directly toxic to brain cells, the researchers discovered that the mutation is initially harmless and does not immediately harm cells. In fact, it can persist for decades without causing any significant effects. However, over time, the CAG repeats grow longer, a process known as somatic expansion, and this gradual accumulation ultimately leads to the formation of a highly toxic version of the HTT protein that causes cell death.
The researchers found that the length of CAG repeats can grow exponentially in the neurons of people with Huntington’s disease. While CAG repeats begin as a relatively short stretch, they can eventually expand into hundreds or even thousands of repeats, a process that accelerates after reaching a critical threshold. Once a striatal projection neuron’s CAG repeat tract grows to about 150 repeats, the cell undergoes significant changes. At this point, the cell’s gene expression becomes severely distorted, leading to dysfunction and eventual death.
Interestingly, the mutation does not immediately harm cells. For the first few decades of life, the CAG repeat expansion progresses slowly, and cells can tolerate it without any noticeable effects. However, once the CAG repeat reaches a certain threshold, the expansion accelerates dramatically, and the neuron quickly becomes toxic and dies. The gradual death of these cells over time is what leads to the cognitive and motor symptoms characteristic of Huntington’s disease.
Implications for Huntington’s Disease Treatment
This new understanding of the disease’s mechanism has significant implications for developing treatments. Many previous drug trials aimed at reducing the production of the HTT protein have failed. One reason for these failures is that, at any given time, only a small proportion of neurons actually contain the toxic version of the HTT protein, which makes it difficult for such treatments to show effectiveness.
The findings of this study suggest that a more effective approach might be to target the DNA repeat expansion itself. By slowing or stopping the CAG repeat from expanding, it may be possible to delay the onset of toxicity and, in turn, prevent the progression of Huntington’s disease.
Steve McCarroll, one of the lead researchers, emphasized that this discovery marks a fundamental shift in how scientists understand the disease. “These experiments have changed how we think about how Huntington’s develops,” he said. “This is a really different way of thinking about how a mutation brings about a disease, and we think that it will apply in DNA-repeat disorders beyond Huntington’s disease.”
Sabina Berretta, co-senior author and associate professor of psychiatry at Harvard Medical School, added that the findings could have a significant impact on relieving the suffering caused by Huntington’s and other genetic disorders involving DNA repeat expansions. “This study and the work it informs could be impactful and make a major difference in relieving suffering in the short term,” she said.
The Key to the Discovery: Single-Cell RNA Sequencing
The breakthrough in understanding how the HTT mutation causes Huntington’s disease was made possible through the use of a powerful technology known as single-cell RNA sequencing. This technique, which was developed by McCarroll’s lab a decade ago, allows researchers to analyze gene expression in individual cells, revealing valuable insights into how DNA repeats expand over time.
In this study, the researchers used single-cell RNA sequencing to study brain tissue donated by 53 people with Huntington’s disease and 50 individuals without the disease. By analyzing more than 500,000 individual brain cells, the researchers were able to determine how CAG repeat tracts changed in length over time and how these changes affected gene expression.
The results were striking. While most cells from individuals with Huntington’s disease had CAG repeats that were similar in length to the version they inherited, the striatal projection neurons – the cells that are most affected in the disease – showed a significant expansion of their CAG repeats. Some neurons had as many as 800 CAG repeats, far beyond the threshold of 150 that triggers cell death.
The study revealed that neurons with CAG repeats longer than 150 began to exhibit profound disruptions in gene expression. Crucially, this discovery highlights the fact that the mutation itself does not directly cause cell death. Instead, it is the gradual expansion of the CAG repeats over time that ultimately leads to neuronal dysfunction and death, which explains why symptoms of Huntington’s disease typically do not appear until later in life.
New Opportunities for Therapeutic Intervention
With this new understanding of the disease, researchers are exploring potential therapeutic strategies that could target the CAG repeat expansion itself. One promising avenue involves slowing or halting the expansion of the repeats. This could be achieved by developing molecular therapies that interfere with the DNA-repair processes that contribute to the expansion of the CAG repeats. By preventing further expansion, it might be possible to delay or even prevent the toxic effects associated with Huntington’s disease.
Previous research has shown that certain proteins involved in DNA repair, such as MSH3, play a role in the expansion of CAG repeats. In some cases, these proteins inadvertently promote the expansion of the repeats, making the disease worse. Understanding how to regulate these proteins could be key to slowing the progression of the disease.
McCarroll and his colleagues are continuing to investigate how the expansion of CAG repeats leads to neuronal death and why certain types of neurons are more susceptible to the toxic effects than others. By understanding these mechanisms in greater detail, researchers hope to develop more effective treatments for Huntington’s disease and other genetic disorders that involve DNA-repeat expansions.
Beyond Huntington’s: The Potential for Treating Other DNA-Repeat Disorders
The significance of this discovery extends beyond Huntington’s disease. More than 50 other human genetic disorders, including fragile X syndrome, myotonic dystrophy, and spinocerebellar ataxia, are caused by expansions of DNA repeats in various genes. These conditions, like Huntington’s, involve the gradual accumulation of DNA repeats over time, leading to disease onset later in life.
By applying the findings from this research to other DNA-repeat disorders, scientists may be able to develop therapies that slow or halt the progression of these conditions as well. As McCarroll noted, “It’s going to take much scientific work by many people to get to treatments that slow the expansion of DNA repeats, but we’re hopeful that understanding this as the central disease-driving process leads to deep focus and new options.”
Conclusion
The discovery of the mechanism behind Huntington’s disease opens up new possibilities for treatment and offers hope to the millions of people affected by the disease. By shifting the focus from targeting the HTT protein to addressing the expansion of CAG repeats in the HTT gene, researchers have identified a potential therapeutic approach that could delay or even prevent the onset of the disease. With continued research and a deeper understanding of the underlying biology, scientists are optimistic that new treatments for Huntington’s and other DNA-repeat disorders will soon be within reach.
Reference: Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease, Cell (2025). DOI: 10.1016/j.cell.2024.11.038. www.cell.com/cell/fulltext/S0092-8674(24)01379-5