Researchers have made a major breakthrough in our understanding of Huntington's disease. This genetic disorder has long been known to be caused by mutations in the huntingtin gene, which leads to the death of brain cells and neurodegeneration. The disease is usually fatal within fifteen to eighteen years of symptom onset, which is typically in a patient's forties. Scientists have long wondered how the mutation can be harmless for so long, only to cause fatal problems at some point. This study has shown that the mutations which lead to Huntington's appear to get worse over time, until they reach a disease-causing threshold. The findings, which could lead to new ways to prevent or treat the disease, have been reported in Cell.
The mutations that cause Huntington's involve a repeat of a three base pair sequence: CAG in the huntingtin gene. In Huntingon's patients, the CAG sequence is repeated forty or more times, instead of fifteen to 35 times in unaffected individuals.
This work has revealed that the CAG repeats of forty or more actually expand further, to reach hundreds of CAG repeats. This involves somatic changes, which occur in the genome during a person's lifetime, and in Huntington's patients, are related to the expression of the huntingtin gene in certain brain cells that end up dying. The cells seem to die once the CAG repeat reaches about 150 times. As these mutation-carrying neurons die off, the symptoms of the disease arise.
Therapies that aim to treat Huntington's by reducing the expression of the mutant gene may not be effective because not many neurons carry the protein with over 150 repeats at any one time. This work has indicated that preventing the expansion of the repeat may be another way to treat the disease.
“These experiments have changed how we think about how Huntington’s develops,” said co-coresponding study author Steve McCarroll, a Professor at Harvard Medical School and Howard Hughes Medical Institute investigator, among other appointments. “This is a really different way of thinking about how a mutation brings about a disease, and we think that it will apply in DNA-repeat disorders beyond Huntington's disease.”
The neurons that die in Huntington's patients are called striatal projection neurons, which relate to movement, cognitive functions, and motivation.
A technology called droplet single-cell RNA-sequencing (Drop-seq), helped make this work possible by revealing the length of CAG repeats in individual cells. Traditional sequencing methods often have a difficult time reliably handling long sequences of repeats, but technologies are advancing.
The researchers were also able to use brain tissue that had been donated by Huntington's patients in this analysis. Some people carried cells with as many as 800 CAG repeats.
“It’s been known that these repeats expand in neurons,” said co-corresponding study author Seva Kashin, a senior principal software engineer. “But the ability to take a particular cell and measure both the CAG length and the transcriptional profile—that’s a really important underpinning that’s allowed for really powerful analysis.”
“It’s going to take much scientific work by many people to get to treatments that slow the expansion of DNA repeats,” McCarroll added. “But we’re hopeful that understanding this as the central disease-driving process leads to deep focus and new options.”
Sources: Broad Institute of MIT and Harvard, Cell