Research headed by scientists at the University of British Columbia has revealed why some people with Huntington disease (HD) may develop an earlier onset, more aggressive form of the disease. The study shows how a particular genetic variant can speed onset of HD motor symptoms by up to 12.5 years and accelerate clinical measures of disease progression by driving runaway DNA changes inside the brain’s most vulnerable neurons.
“People with this genetic variant have dramatically hastened onset of disease, but we didn’t know why,” said Michael Hayden, MBChB, PhD, professor at the Centre for Molecular Medicine and Therapeutics at UBC. “This work answers that question and provides dramatic evidence that repeated expansion of the mutation is an important driver of Huntington disease and a potential treatment target.” Hayden is senior author of the researchers’ published paper in Neuron, titled “Loss of interruption in the HTT CAG repeat is associated with increased somatic expansion and loss of medium spiny neurons in HD.”
Huntington disease is a rare, inherited neurological disorder that causes the progressive breakdown of nerve cells in the brain. The condition affects movement, thinking and emotional well-being, and there is currently no cure or treatment to slow progression.
One way to think about the process is like a typo in a document that keeps getting copied. With every copy, the mistake is replicated and interferes with the message. “HD is caused by 36 or more uninterrupted CAG repeats in exon 1 of the Huntingtin gene (HTT), and the number of inherited CAG repeats is the primary determinant of the age at which symptoms first emerge,” the authors explained.
In Huntington disease the mutation continues to repeat and expand within neurons over time. As those repeats become longer, they interfere with normal cell function and make brain cells increasingly vulnerable to damage and death. “Medium spiny neurons (MSNs) are gradually lost in HD and undergo selective somatic CAG expansion, but it is unclear how somatic expansion relates to MSN pathology,” they continued.
Hayden added, “When we looked at the neurons that are dying in Huntington disease, we saw much greater expansion of the genetic mutation. This continues to strengthen the argument that DNA expansion is an important cause of disease.”
A small proportion of people with HD have a particular genetic variant, and researchers have known for years that these individuals develop Huntington disease earlier in life. “CAG and CCG loss-of-interruption (CAG-CCG LOI) variant hastens the onset of HD motor symptoms by up to 12.5 years and accelerates clinical measures of disease progression when compared with patients with the canonical sequence,” the team noted.
But it wasn’t known why this seemingly small change in DNA had such a dramatic effect on disease onset and progression. People carrying the variant had dramatically larger expansions of the Huntington mutation inside their neurons, occurring about five times more frequently than in patients without the variant. They also had fewer surviving neurons and earlier loss of particularly vulnerable nerve cells.
For their reported study the researchers analyzed blood samples and post-mortem brain tissue. “Here, we apply complementary approaches to assess somatic HTT CAG expansion from peripheral blood, postmortem brain tissues, and isolated MSNs of HD patients with and without the CAG-CCG LOI modifier variant and quantify MSN loss in the CAG-CCG LOI donor caudate.” They found a clue that helps explain one of the mysteries of Huntington disease, which is why a mutation that is present in every cell of the body primarily damages the brain.
Although the mutation exists throughout the body, the researchers found that the expansion process appears to be highly concentrated in certain cells of the brain. Blood samples, by contrast, showed little evidence of the dramatic changes that take place within the brain’s neurons. “Our interrogations of somatic expansion in blood, brain, and striatal MSNs of donors with and without the CAG-CCG LOI show this modifier does not increase small expansions in blood or bulk brain tissues, yet profoundly increases the proportion of genomic large (111–150) and very large (>150) CAG expansions in affected striatal MSNs,” they wrote.
“The mutational expansion seems to be selective for the brain,” Hayden added. “That may help explain why Huntington disease, even though the mutation is in every cell, is fundamentally a brain disease.”
The findings suggest blood tests are not a reliable indicator of the disease unfolding inside the brain, which is an important consideration for future Huntington disease research and clinical trials. “Peripheral blood DNA does not capture increased somatic expansion in MSNs, suggesting that blood DNA is a poor biomarker for disease-relevant somatic expansion in HD-affected neurons,” they noted.
While other factors besides expansion likely contribute to neuron loss, the findings provide some of the strongest human evidence to date that expansion of the Huntington mutation is a key factor in disease progression. “It validates repeat expansion of the DNA as an important therapeutic target in Huntington disease,” Hayden said. “If we can suppress that expansion, it may be possible to delay progression or delay the onset of disease.” And as the authors further commented, “Our study further underscores the need for cell-type-specific studies across other repeat expansion disorders that preferentially affect specific neuron populations.”
Several experimental therapies in development aim to slow or prevent this mutation growth before the damage occurs. While more research is needed, this study’s findings show research is moving in the right direction for a disease which has been so difficult to treat.
