New findings shed light on cause of Huntington's disease progression

A new study of nerve cells affected by Huntington’s disease (HD) reveals that the disease-causing gene slowly expands over time but doesn't start causing harm until it hits a toxic threshold that rapidly leads to the nerve cell’s death.

HD has long been a particularly vexing genetic disorder. While the variant of the huntingtin gene that causes it is inherited and present from birth, it doesn’t cause neurological symptoms until much later in life.

The researchers, led by Steven McCarroll, Ph.D., of the Broad Institute of MIT and Harvard, suggest that stopping the gene’s expansion could be the key to developing effective therapies. The results were published in Cell on Jan. 16.

A characteristic part of the huntingtin gene is a series of repeated DNA segments made up of cytosine, adenine and guanine (CAG). This gene makes a protein with an unclear function, but it seems to be important for nerve cells. Having a gene with 40 or more CAG repeats leads to HD around middle age, when nerve cells called striatal projection neurons (SPNs) begin to die. This initiates a range of movement and cognitive symptoms that is ultimately fatal.

To discern how CAG repeats cause HD, McCarroll’s team examined SPNs from the brains of patients who died while in different stages of the disease. To their surprise, they found that the length of CAG repeats in the huntingtin gene of SPNs grew over a patient’s life, slowly at first but then expanding rapidly after reaching about 80 repeats.

This repeated growth didn’t have much effect on the patients until the gene mutated in size to more than 150 repeats. At this point, other genes that are normally turned off in SPNs begin to activate, including genes involved in programmed cell death.

“Our results suggest that an SPN’s own CAG repeat becomes toxic only when quite long,” the researchers wrote, “and that this long repeat is necessary and sufficient for pathology.”

The authors suggest that reducing the expression of the huntingtin protein might not be effective at treating HD because the number of cells experiencing toxic effects of long CAG repeats at any one time is low, and, once a cell reaches that point, it may be too late to save it for very long.

Instead, therapies could focus on slowing the growth of repeats; given how long it takes for the repeats to reach a toxic length, the authors write, “even modestly slowing somatic expansion might substantially postpone HD symptom onset.”