Researchers with the Lawrence Berkeley National Laboratory have made a breakthrough in the field of treatments targeting Huntington’s disease, a fatal neurodegenerative disease with no known cure.
In a study published in the journal Nature Communications in May, researchers hypothesize a specific kind of DNA damage that kills brain cells is associated with Huntington’s disease — and they’ve tested a compound that could salvage weakened brain cells.
Huntington’s disease can cause uncontrolled movements and affect a patient’s cognitive and mental health. Symptoms worsen over time; the disease is ultimately fatal.
Huntington’s is hereditary, meaning it gets passed down from a parent to their child. It is caused by a defect in the gene that produces a protein called huntingtin. Existing research says the defected gene eventually results in the production of a mutated form of huntingtin. Existing research was uncertain about the link between the mutation and the neurodegeneration.
Now, Berkeley Lab researcher Aris Polyzos said the team might have discovered another factor of the telltale brain cell death associated with Huntington’s: double-strand DNA breaks.
Double-strand breaks are particularly damaging because they can happen across a cell’s entire genetic code, meaning it’s a widespread threat, said Cynthia McMurray, who has been studying Huntington’s for the past 15 years and is one of the Berkeley Lab study’s authors.
“It’s dangerous because it leads to actual snapping of the DNA,” Polyzos said. “There’s this clean break across the DNA. And we think (that) if you get enough of those, the cell will die.”
Double-strand breaks are caused by a sort of “toxic exhaust,” according to Polyzos. When cells generate energy via fatty acids instead of glucose, they produce more harmful molecules — the “toxic exhaust” — that stick to DNA and can cause damage such as double-strand breaks.
While organisms have developed ways to mitigate that damage, researchers noticed more of this “toxic exhaust” in brain cells of mice with Huntington’s disease than those without, and along with it, more double-strand breaks.
Normally, the huntingtin protein binds to enzymes that repair double-strand breaks, but researchers found that its mutated form interferes with that process, McMurray said. From there, the breaks accumulate.
Researchers then tried to minimize breaks by injecting mice with an antioxidant, which stops harmful molecules in their tracks. The antioxidant they used works much like natural compounds such as vitamin C and zinc, which counteract possible damage to cells.
The results were promising: After injecting the mice with the antioxidant, Polyzos said he saw less double-strand breaks.
The antioxidant also stopped the degradation of DNA in brain cells and prevented motor function from declining — it was able to reverse some of the symptoms of Huntington’s disease.
McMurray said the team hopes to bring this treatment to human trials down the line.
“What this discovery says is now we have something — there are compounds already existing today that can target and remove a double-strand break. So this gives us a whole new idea that if we can do that, it may lead to a cure,” McMurray said.