Understanding the Genetic Culprit of Huntington Disease
For more than three decades, the defective HTT gene has been blamed by scientists for Huntington disease, a neurodegenerative disorder that progressively destroys brain cells. The genetic defect causes debilitating symptoms such as cognitive decline, psychological problems, and uncontrolled movements. But one thing has poorly been understood-the reason for the late onset of the disease-until now.
A new study published in Cell reports that an expanding stretch of DNA in brain cells plays a pivotal role in disease progression. These findings can explain why symptoms appear later in life and also why the disease progresses at different rates among individuals.
The Genetic Mechanism Behind Huntington Disease
People with Huntington inherit a faulty version of the HTT gene, which codes for the huntingtin protein. The gene has a repeating pattern of three DNA nucleotide bases-cytosine, adenine, and guanine, or CAG-repeated consecutively. Whereas most people have 15-30 CAG repeats and never develop Huntington’s, individuals with 40 or more repeats will almost always develop symptoms in later life.
This genetic stutter causes the huntingtin protein to become abnormally large and unstable, and these accumulate in clumps inside brain cells. Over time, this leads to the death of neurons, especially in the striatum, part of the brain that influences movement and motivation.
A Hidden Process: Somatic Expansion
Until recently, the scientific community thought that the number of CAG repeats one had was solely due to inheritance. In 2003, however, came a surprise: the number of CAG repeats actually increases throughout a person’s lifetime, especially in the brain cells. This process, termed somatic expansion, was especially prominent in the striatum, with some cells accumulating up to 1000 repeats, far more than at birth.
For years, the role of somatic expansion in Huntington disease had not been as clear. Many researchers had assumed that long-term exposure to the mutant huntingtin protein caused a gradual death of neurons. However, recent findings beg to differ.
The Role of the “Ticking DNA Clock”
To understand the relationship between somatic expansion and Huntington disease better, researchers looked at brain tissue from 103 donors, both those with and without Huntington. Using computer modeling and RNA analysis, the team tracked genetic changes in more than 500,000 single cells.
Their findings indicated a very unusual course of progression in the neurons affected by Huntington. For about two decades, the CAG repeats in the HTT gene expanded very slowly. Once the sequence reached a length of about 80 repeats, however, the expansion dramatically accelerated. In only a few years, the sequence often expanded to 150 repeats—a toxic threshold beyond which neurons deteriorated and died in a matter of months. This type of progression has been likened to a “ticking DNA clock”: neurons die once the clock runs out.
Explaining the Delayed Onset and Variable Progression
Another insight into Huntington disease comes from the “ticking DNA clock”. Symptoms show up at midlife because it takes decades for the expansion process to reach a critical threshold in enough neurons. The variation in the rate at which repeats accumulate also explains why the progression of the disease varies in each individual.
This patchwork damage across the striatum corresponds with the variety of symptoms in Huntington patients. Some neurons cross the toxic threshold before others, resulting in remarkable variation in disease severity and timing of disease progression.
Potential Treatment Strategies
The discovery of the role of somatic expansion opens new avenues for treatment. Research has identified certain enzymes that participate in the process of expansion. These enzymes, which normally are involved in repairing DNA errors, sometimes make the wrong move and insert extra CAG repeats. In theory, targeting these enzymes could slow or prevent somatic expansion and offers a promising alternative to existing therapies aimed at eliminating the mutant huntingtin protein.
Enzyme Suppression Therapy
One very promising target for therapy is MSH3, an enzyme involved in the process of somatic expansion. Researchers are investigating suppression of MSH3 in mouse models to stop the toxic expansions of the CAG repeats. Though these treatments are early-stage, they may offer hope someday to symptomatic patients.
A Dual Approach
It may be that combining therapies to target both somatic expansion and mutant huntingtin protein production will maximize the treatment benefit. Such a strategy may rescue the 95% of neurons that remain unaffected in the early stages of the disease, even after symptoms appear.
Moving Toward the Clinic
The new research marks a quantum leap in the study of Huntington, and for the first time brings together decades of information about somatic expansion. Findings like this, says Sarah Hernandez with the Hereditary Disease Foundation, point to new routes for innovative therapies. “This is certainly going to drive new theories to the clinic,” she says.
While one would wonder why this accelerating expansion should be happening particularly beyond 80 repeats or especially involve the striatum, it opens an avenue toward treatment methods someday that can really improve life among people afflicted by Huntington’s disease.
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