Breakthrough Discovery Unveils How Huntington’s Disease Progresses Over Decades

The mutation in the huntingtin (HTT) gene, responsible for the incurable, dominantly inherited Huntington’s disease, was identified decades ago. However, understanding how this triplet repeat expansion mutation leads to the disease has long eluded scientists—until now.

A collaborative team of researchers from the Broad Institute, Harvard Medical School, and McLean Hospital has uncovered how the mutation triggers symptom development later in life. This discovery could pave the way for novel therapeutic approaches to delay or prevent the onset of Huntington’s disease.

The study, published in Cell and titled “Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease,” reveals that the HTT gene mutation is initially harmless but gradually transforms into a toxic form that kills specific brain cells.

The research, co-led by Steve McCarroll, PhD, of the Broad Institute, Harvard Medical School, and the Howard Hughes Medical Institute, and Sabina Berretta, MD, of Harvard Medical School and McLean Hospital, aims to better understand how the gene mutation affects cell health and symptom development.

“The point of our work—what we all do—is relieving suffering caused by disease,” said Berretta.

How the Mutation Works

The HTT gene contains repeated sequences of CAG, which codes for the amino acid glutamine. In healthy individuals, there are typically 15 to 35 CAG repeats. However, in Huntington’s patients, this sequence expands to over 40 repeats.

The study’s authors developed a single-cell technique to measure the repeat length alongside genome-wide RNA expression. They discovered that neurons in the striatum of the brain are particularly susceptible to this condition, experiencing “somatic expansion,” where the CAG repeat count grows larger. Once the number surpasses 150 repeats, cells become dysfunctional and eventually die.

Single-cell RNA sequencing was used to analyze over 500,000 cells from the brain tissues of 53 individuals with Huntington’s disease and 50 healthy controls. The results indicated that only striatal projection neurons, the disease’s primary targets, develop significant CAG repeats. Moreover, when a cell’s gene reaches about 80 repeats, the repeat count increases rapidly, typically reaching 150 repeats within a few years.

McCarroll noted, “These experiments have changed how we think about how Huntington’s develops.” The findings highlighted that the unstable alleles expand to more than ten times their original length over decades.

Seva Kashin, co-first author from the Broad Institute, emphasized the importance of their technique, which allowed them to measure both the CAG length and the transcriptional profile of a specific cell, providing a powerful underpinning for their analysis.

Preventing Symptoms

The researchers’ work identifies key points at which therapeutic interventions can occur. According to Bob Handsaker, co-first author from the Broad Institute, this discovery fills in many gaps in the understanding of Huntington’s disease pathology.

Advancements in therapy traditionally focus on reducing HTT expression, much like reducing the expression of a mutation would reduce the disease’s progression and symptoms. However, this approach has shown limited success.

The study reveals the entire life span of the affected neuron before cell death, offering much more time for potential therapeutic applications. If a treatment could modestly slow the DNA-repeat expansion, it might significantly delay the onset of Huntington’s disease symptoms.

The findings suggest that therapies aimed at reducing expansion could impact many more cells, delaying or even preventing the onset of the disease. These interventions could potentially slow progression in individuals already exhibiting symptoms.

While significant progress has been made, many questions remain unanswered. Ongoing research aims to understand why repeats expand more rapidly in some neurons than others and how CAG repeats exceeding 150 initiate cell death. This continued work could uncover additional avenues for symptom prevention and treatment.

“It’s going to take much scientific work by many people to get to treatments that slow the expansion of DNA repeats,” McCarroll said. “But we’re hopeful that understanding this as the central disease-driving process leads to deep focus and new options.”

Berretta highlighted the importance of patient participation in research. “This would not have been possible without the altruism of many brain donors who have left a legacy of knowledge that will last and benefit many other people,” she said.