A groundbreaking study has uncovered new insights into the progression of Huntington’s disease, a devastating neurodegenerative disorder that affects brain cells. Researchers have discovered that a “ticking DNA clock” within brain cells linked to huntington’s disease, explaining why symptoms take years to develop and why the severity can vary significantly between individuals.

The Genetic Cause Behind Huntington’s Disease

Huntington’s disease is caused by a defective version of the HTT gene, which produces the huntingtin protein. The HTT gene contains a repeated sequence of three nucleotide bases—cytosine, adenine, and guanine (CAG). Most people inherit between 15 and 30 CAG repeats and remain unaffected. However, those with 40 or more CAG repeats almost always develop Huntington’s disease later in life, experiencing psychological and cognitive issues along with involuntary movements called chorea.

The increased number of repeats leads to an abnormal form of the huntingtin protein that clumps inside brain cells, causing damage. The longer the stretch of repeats, the earlier symptoms appear. For years, scientists believed the number of CAG repeats only expanded when passed from parent to child, leading to earlier onset in successive generations. However, further research revealed that the length of CAG repeats can continue expanding throughout a person’s lifetime, particularly in certain brain cells.

Discovery of the Ticking DNA Clock And Brain Cells Linked to Huntington’s Disease

The new study, published in Cell, builds on earlier findings that observed massive CAG expansions in the striatum, a brain region critical for movement and motivation that is severely damaged in Huntington’s disease. Some brain tissue samples showed over 1000 CAG repeats, a level impossible to be present at birth.

To investigate how these expansions occur over time, researchers analyzed brain tissue from 53 individuals with Huntington’s disease and 50 without. They measured the activity of the HTT gene in over 500,000 individual cells using postmortem brain samples. The results revealed that brain cells with around 40 or more CAG repeats initially expanded very slowly over two decades. However, once the repeat count reached around 80, the expansion accelerated rapidly, reaching a toxic threshold of approximately 150 repeats.

At this point, neurons began to deteriorate rapidly, losing essential gene functions and dying within months. This cellular breakdown may explain why symptoms often emerge in midlife, after decades of slow damage buildup.

Why Symptoms Develop Differently for Each Person?

The study also sheds light on why Huntington’s disease varies in severity among individuals and Brain Cells Linked to Huntington’s Disease . Not all neurons accumulate expanded repeats at the same rate. Some cells cross the toxic threshold earlier than others, leading to a patchy pattern of damage across the brain. This variability could explain the wide range of symptom onset and progression observed in people with Huntington’s disease.

While the findings clarify how CAG expansions progress over time, the exact reasons why expansions accelerate after 80 repeats remain unclear. Researchers also noted that while the striatum is most affected, other brain regions show damage as well, albeit less severely.

Potential for New Treatment Strategies

The discovery offers promising directions for new treatment approaches. Scientists have identified specific enzymes involved in the expansion of CAG repeats during DNA repair processes. When errors occur during the production of the huntingtin protein, these enzymes mistakenly insert extra CAG repeats while attempting to fix the error.

Targeting these repair enzymes could prevent further expansion of the repeats. One enzyme, MSH3, has shown potential as a target in mouse studies, though human trials are yet to begin. Unlike previous strategies aimed at eliminating the mutant huntingtin protein entirely, enzyme-targeting therapies could protect neurons from further damage even after symptoms appear.

Since most neurons affected by Huntington’s disease do not reach the toxic threshold simultaneously, this approach might help patients who are already symptomatic. Researchers believe that even in advanced stages of the disease, most neurons remain viable and could potentially be preserved with the right intervention.

Moving Towards a Dual-Therapy Approach

Experts are optimistic that combining treatments targeting both the genetic expansion and the mutant huntingtin protein could yield even better results. A dual-pronged approach might slow disease progression significantly and protect a greater number of neurons from damage.

The findings mark a major step forward in Huntington’s disease research, Brain Cells Linked to Huntington’s Disease potentially transforming the way the disorder is treated. With continued progress, therapies that directly address the underlying genetic mechanisms may become a reality, offering new hope for those affected by this devastating condition.