Huntington's may be a DNA-damage disease, not just a gene disease, Berkeley Lab finds in mice

A Berkeley Lab mouse study, published Monday in Nature Communications, traces neuronal loss in Huntington’s disease to a source other than the mutant huntingtin protein: the trail of broken DNA the protein leaves behind, scattered across the genome, in cells that were supposed to repair the damage and did not.

Huntington’s is a fatal inherited neurodegenerative condition in which a mutated form of a protein called huntingtin causes neurons in parts of the brain to die, typically in midlife. The dominant research target for thirty years has been the mutant protein and the way its CAG trinucleotide repeat, a three-letter DNA sequence copied too many times, expands inside neurons as the disease progresses. A team at Berkeley Lab argues that target is incomplete.

The team, co-led by biochemist Aris Polyzos and retiree-affiliate Cynthia McMurray, both in the lab’s Biosciences Area, found that mutant huntingtin suppresses a repair pathway called nonhomologous end joining, or NHEJ, the cell’s main way of reattaching the two ends of a severed DNA strand. When that pathway is impaired, double-strand breaks, or DSBs, pile up. The result, in the HdhQ(150/150) mouse model, which carries a human-style expanded huntingtin allele, is a slow accumulation of genomic damage that, in the paper’s read, drives the neuronal loss and behavioral decline that defines the disease.

“Double-strand DNA breaks are a major and previously underappreciated cause of Huntington’s disease neuropathology,” Polyzos said in the lab’s release. “The fact that the same breaks are observed even in mice that cannot somatically expand their inherited allele shows that this is an independent mechanism, not a consequence of the CAG expansion.”

For thirty years, drug discovery in Huntington’s has run on one rail: silence the mutant gene, shrink the huntingtin protein, or stop the CAG repeat from expanding further inside neurons. The Berkeley Lab work does not displace that rail; it adds a second one. In animals engineered so the inherited allele cannot expand, DSBs and the resulting transcriptional dysfunction still appeared. Treating the DNA-damage axis therefore addresses a population the gene-targeting drugs do not reach: people whose huntingtin mutation is already in place and not expanding further.

In HdhQ(150/150) mice, treatment with an investigational antioxidant reduced DSBs, eased neuronal damage, and reversed disease symptoms. The mutant huntingtin gene and its CAG repeat were untouched. The compound is not named in the lab’s release or in the public version of the paper. McMurray, who spent years at the Mayo Clinic before joining Berkeley Lab, called it a possible “new way to treat Huntington’s patients” that does not try to edit or silence the gene.

Peer review in Nature Communications takes the result past the May 2025 bioRxiv preprint. The field now has a concrete, citable therapeutic axis, DNA-damage and antioxidant rather than gene-silencing, to plan around. The result is in a single mouse line, the antioxidant is not identified in the public materials, and human translation is years out. Huntington’s remains fatal, inherited, without a cure, and served, when it is served at all, by a small set of experimental options.

Past and ongoing treatments target the gene or its expansion, Polyzos said. This one does neither, and it still works in mice. The work now needs the antioxidant named in a public filing and the DSB finding reproduced in human neurons.