DNA damage points to a new Huntington’s treatment path in mice

The red spots on a microscope image of a mouse brain mark something the researchers did not expect to see in such abundance: broken DNA inside neurons. In a study led by Lawrence Berkeley National Laboratory, scientists found a marked accumulation of double-stranded DNA breaks in the striatum, the brain region most severely affected by Huntington’s disease, before the animals developed its hallmark symptoms.

Huntington’s is caused by a mutated copy of the huntingtin gene, which contains extra repeated sequences. Those repeats can expand over a patient’s lifetime, and a greater number of repeats is linked to earlier onset and more severe disease. The Berkeley Lab team’s finding adds another mechanism to the picture: ongoing DNA damage may help drive the death of neurons rather than merely appearing after symptoms have begun.

The researchers, including biochemist Aris Polyzos and Huntington’s disease expert Cynthia McMurray, followed a metabolic clue. In their mouse model, support cells in the striatum took up less glucose, the brain’s standard fuel, and switched to fatty acids to produce energy. When mitochondria break down those fatty molecules, they generate reactive oxygen species, byproducts that can attack DNA and cause strands to break.

The team then treated the mice with an investigational antioxidant. The treatment suppressed the DNA breaks and rescued the animals from neuronal damage and disease symptoms, without editing the huntingtin gene, shortening its repeats or blocking its expression. That matters because those are the main strategies pursued by earlier and ongoing experimental treatments, according to the researchers.

So what changes, concretely? The work points to a treatment route aimed at protecting neurons from the damage caused by the mutation, rather than trying to alter the mutation itself. Clinical agents that affect these DNA breaks already exist for humans, McMurray said, which could make the approach easier to test. But the evidence remains preclinical: the next step is to reproduce the findings in human cells and show that neurons can be protected before any clinical trial can be justified.