A groundbreaking study has shed new light on the origins of Huntington’s disease, offering valuable insight into how this devastating genetic disorder develops. Huntington’s disease, a hereditary and fatal condition, leads to the gradual breakdown of nerve cells in the brain, severely impairing movement, cognition, and behavior. Although the genetic mutation responsible for the disease has been known for years, scientists have struggled to understand why symptoms do not appear until later in life, despite the mutation being present from birth.
Recent research has unveiled an unexpected explanation: the mutation, initially harmless, slowly evolves over time. Eventually, it reaches a critical threshold that triggers the production of toxic proteins, leading to the death of brain cells.
“The long-standing puzzle in the field has been why a genetic disorder with a clear cause can manifest only later in life,” said Dr. Mark Mehler, Director of the Institute for Brain Disorders and Neural Regeneration at Albert Einstein College of Medicine. Although Dr. Mehler was not involved in the study, he called the findings a “landmark” discovery that addresses many unresolved issues in Huntington’s disease research.
Symptoms of Huntington’s disease typically emerge between the ages of 30 and 50 and worsen over 10 to 25 years. These symptoms include involuntary movements, an unsteady gait, personality changes, and impaired judgment.
A team of scientists from the Broad Institute of MIT and Harvard, McLean Hospital in Massachusetts, and Harvard Medical School studied brain tissue from 53 individuals with Huntington’s disease and 50 controls, analyzing over 500,000 cells. The researchers focused on a mutation in the gene that encodes the huntingtin protein, where a segment of DNA containing a three-letter sequence, “CAG,” is repeated. In individuals with Huntington’s, this sequence is repeated 40 or more times, while in healthy individuals, the repetition typically ranges from 15 to 35.
The researchers discovered that these DNA repeats expand progressively over time. Initially, the repeats grow slowly, but once they surpass a threshold of approximately 150 repeats, they begin to produce toxic proteins that harm brain cells. The study’s findings, published Thursday in Cell, represent a major step forward in understanding how the mutation progresses into a fatal disease.
“We were surprised by how quickly the repeats expand once they reach a critical mass,” said Steve McCarroll, a co-senior author of the study. “This discovery opens up new avenues for targeting the disease at an earlier stage.”
The research also suggests that the expansion of these DNA repeats accelerates after they reach around 80 repeats, with the severity of the disease’s onset correlating with the number of repeats.
The new findings also help explain why previous attempts to develop treatments aimed at reducing the toxic huntingtin protein have faced challenges. Since only a small number of cells contain the harmful protein at any given time, efforts to target this protein may not be sufficient. Instead, researchers believe that slowing or halting the expansion of the CAG repeats may be a more effective strategy for addressing the disease.
Despite the hurdles, McCarroll remains optimistic. “Many companies are already exploring strategies to stop or slow the DNA repeat expansion,” he said. “Though there are no guarantees, this could lead to new therapies for people with Huntington’s.”
With an estimated 41,000 Americans currently affected by Huntington’s disease, the search for effective treatments remains urgent. Currently, there is no cure, and available medications only help manage symptoms. However, the recent findings offer new hope that a better approach to treatment may be on the horizon.
Related Topics
