New Delhi: A discovery by Lawrence Berkeley National Laboratory reveals a new class of treatments for Huntington’s disease.
Huntington’s disease (HD) is a fatal, inherited brain disorder that causes nerve cells in the brain to break down and die over time, damaging the parts of the brain that control movement, thinking, and feelings.
The study, published in Nature Communications, found that an additional, previously overlooked characteristic of Huntington disease appears to be driving the neurodegeneration – a marked increase in breaks across DNA strands throughout the genome.
People with the disease carry a mutated copy of a protein-coding gene which contains many extra nucleotides – building blocks of DNA – in a repeating sequence.
After nearly 30 years of research focused largely on fixing the genetic mutation behind Huntington’s, the work from Berkeley Lab highlights another aspect of the disease that could be targeted using existing compounds.
“Despite years of work worldwide, there’s no cure for Huntington’s, and only limited, experimental treatments. We’re excited to add another piece to the puzzle for this disease, which has proven to be frustratingly complex for a condition caused by a single gene mutation,” said Aris Polyzos, a biochemist research scientist in Berkeley Lab’s Biosciences Area.
Polyzos co-led the work alongside senior lead Cynthia McMurray, a retiree affiliate in the Biosciences Area.
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DNA damage before symptoms
The researchers found that DNA damage occurs before the onset of symptoms.
“We show that symptoms are preceded by DNA damage, and that this can be reversed using an investigational antioxidant compound, which also protects against neurodegeneration. This alleviation occurs even without altering or blocking the gene, or stopping the expansion of the mutation, which are the approaches that past and ongoing investigational treatments have taken,” Polyzos said.
McMurray has spent decades studying the genetic and cellular changes underlying HD, first at the Mayo Clinic and later at the Berkeley lab.
“I believe we’re opening the door to a new way to treat Huntington’s patients. Clinical agents already exist for humans that are known to change these breaks. We love that these could be easily tested and lead to a therapeutic strategy more quickly. And the simplicity of the approach is beautiful,” said McMurray.
New insights into how the disease affects brain cells
McMurray and Polyzos began studying energy uptake in HD neurons about 10 years ago, following research that metabolic changes occur in the brains of HD patients before symptoms begin.
Using a mouse model of the disease, the team found that support cells in the brain region most severely affected by HD took up less glucose, the brain’s primary source of fuel. Instead, they switched to breaking down fatty acids to produce ATP (adenosine triphosphate), the molecule that provides energy to cells, for themselves and the neurons that depend on them.
The findings have already drawn interest from other HD researchers, with scientists now looking to understand whether the same mechanism could be targeted in human patients.
“The first step is to establish that the same disease mechanism that was curable in the mouse also occurs in humans,” the researchers wrote in the study.
(Edited by Maryam Hassan)