Berkeley Lab scientists reversed Huntington’s disease symptoms in mice using an experimental antioxidant compound that prevents double-stranded DNA breaks, according to research published in Nature Communications. The study, co-led by biochemist research scientist Aris Polyzos and retiree affiliate Cynthia McMurray, identified accumulated DNA breaks in striatal neurons as a driver of the fatal condition.
Huntington’s disease stems from an inherited mutation that adds repeating nucleotide sequences to the huntingtin gene. Working with colleagues from the Harvard T.H. Chan School of Public Health, the team found that support cells for striatal neurons reduced their glucose uptake and switched to metabolizing fatty acids. This metabolic shift produced reactive oxygen species that caused severe double-stranded DNA breaks. The researchers found that mutant huntingtin protein binds to DNA repair enzymes and suppresses their repair activity, allowing breaks to accumulate.
McMurray and her colleagues showed that this suppression of DNA repair happens separately from the somatic expansion of nucleotide repeats. The team tested two mouse lineages carrying the mutated gene; even when repeat expansion was blocked artificially, the mice still accumulated double-stranded DNA breaks, showed motor symptoms, and died.
The researchers administered daily infusions of XJB-5-131, a synthetic antioxidant developed by Peter Wipf at the University of Pittsburgh that crosses the blood-brain barrier to target mitochondria. The treatment reduced double-stranded breaks, prevented motor function deficits, and lowered inflammation in the mouse brains.
Polyzos is now leading a follow-up study using patient-derived induced pluripotent stem cells differentiated into neurons to evaluate the mechanism in human cells. The National Institutes of Health supported the research project.
