New Research Unveils Unexpected Mechanism of Genetic Mutation Behind
Researchers have uncovered a critical understanding of Huntington’s disease in a groundbreaking study published on January 16, 2025. The study sheds light on why symptoms of this fatal neurodegenerative disorder typically appear only in midlife, despite patients being born with the mutation. Conducted by scientists at the Broad Institute of MIT and Harvard, Harvard Medical School, and McLean Hospital, the findings reveal a slow progression of genetic changes that accelerate in later decades, leading to cell death.
Huntington’s disease arises from a mutation in the Huntingtin (HTT) gene, where a three-letter DNA sequence—CAG—is repeated at least 40 times. These repetitions slowly expand in specific brain cells over decades before becoming toxic, killing the cells rapidly and leading to the disease’s characteristic symptoms.
The research team analyzed brain tissue from 53 people with Huntington’s and 50 without the disease. They observed that most brain cells retained the same number of CAG repeats as inherited. However, striatal projection neurons, which are central to movement and cognitive functions, showed significant expansion of CAG repeats. In some cases, these neurons exhibited as many as 800 repeats, a stark increase from the inherited baseline.
Using advanced computational modeling, the scientists estimated the timeline of these expansions. During the first two decades of life, CAG repeats grow very slowly, at a rate of less than one per year. Once the number of repeats crosses 80, typically after several decades, the process accelerates. The repeats can reach a toxic threshold of 150 in a matter of years, causing the neurons to die within months.
This slow progression helps explain why Huntington’s disease symptoms often remain absent until midlife. It also highlights why symptoms worsen progressively, as different neurons hit their toxicity threshold at varying times.
The study has major implications for potential treatments. Current drugs targeting the HTT gene or its protein products have shown limited success. Researchers believe this may be because only a small fraction of cells harbor the toxic form of the gene at any given time. A new therapeutic approach could focus on halting or slowing the expansion of CAG repeats, potentially delaying or preventing the disease.
“This discovery reframes how we think about Huntington’s disease and other DNA-repeat disorders,” said Steve McCarroll, co-senior author and director of genomic neurobiology at the Broad Institute. “By understanding the slow progression of these repeats, we gain many opportunities to intervene before the disease becomes catastrophic.”
The findings also have implications for related disorders, such as fragile X syndrome and myotonic dystrophy, which involve similar DNA-repeat abnormalities. Researchers are now exploring how other proteins involved in DNA repair and maintenance might be targeted to slow CAG expansion.
This study was made possible by the generous contributions of Huntington’s patients who donated brain tissue. “Our gratitude lies with the families who made this difficult but selfless decision,” said Sabina Berretta, co-senior author and director of the Harvard Brain Tissue Resource Center. “Their legacy of knowledge will benefit countless others.”
While much work remains, the researchers are optimistic about the possibilities. Understanding the genetic mechanics behind Huntington’s provides a roadmap for new therapeutic strategies. By slowing or halting the genetic changes that drive the disease, scientists hope to improve outcomes for patients and their families.
This milestone marks a significant step forward in understanding the mysteries of Huntington’s disease and opens the door to more targeted and effective treatments in the future.
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