Revealed: Why the fatal Huntington’s gene takes so long to cause harm

A mutation in neurons grows for decades before it reaches a deadly limit

Huntington's is an incurable genetic condition that affects neurons that control movement and cognition.Credit: Zephyr/Science Photo Library

Why do people who inherit the brain disease Huntington’s often only show symptoms well into adulthood, between 30 and 50 years of age? The answer lies in a faulty DNA-repair mechanism in neurons that ramps up until the number of errors hits a critical threshold and the neurons start to die¹.

A study of the neurons hit hardest by the disease, published in Cell today, suggests that DNA-repair proteins could be promising targets for the treatment of Huntington’s disease, as well as dozens of similar genetic disorders. Targeting these proteins “has the potential to delay disease onset or slow its progression”, says Christopher Pearson, a human molecular geneticist at the Hospital for Sick Children in Toronto, Canada.

Huntington’s is an incurable and fatal genetic condition that progressively affects movement, balance and cognition. It is caused by an inherited mutation in an allele of the HTT gene, in which a sequence of 3 DNA bases, C, A and G, is repeated at least 36 times.

Long lead

To understand why it takes so long for this inherited mutation to have a detrimental effect, neuroscientist Sabina Berretta at Harvard Medical School in Boston, Massachusetts and geneticist Steven McCarroll at the Broad Institute of MIT and Harvard, in Cambridge, Massachusetts, and their colleagues took a close look at what was happening in the brain.

The researchers looked at the CAG profiles of neurons in a specific brain region of six people who died with Huntington’s and donated their bodies to research. They developed a technique that could determine how many CAG repeats had accumulated in a single nucleus— even very long strings of repeats — and simultaneously sequence all the RNA transcripts in that nucleus. The number of CAG repeats in most neurons was not far off how many they were born with, but specific neurons thought to be the first to die in the course of Huntington’s — striatal projection neurons — had accumulated vastly more repeats by the time of death. Up to 98% had amassed some 60–73 CAGs, and a few had hundreds.

Neurons can accumulate these repeat errors when DNA is split apart to make RNA but the two strands don’t zip back up correctly, creating a loop on one side. DNA-repair proteins then come along to ‘fix’ the problem, but often add sequences that didn’t previously exist.

Neurons that had accumulated more than 150 CAGs drastically changed. Initially, they stopped expressing genes that distinguished them from other types of neuron — a form of identity loss — and then they activated other genes, including some known to promote cell death. “The neurons die soon after,” says Sarah Tabrizi, a physician-scientist who studies Huntington’s at University College London.