.jpg)
Co-lead author and Huntington’s disease expert Cynthia McMurray, right, examines samples in her lab with fellow author Jung Hyun Yoo.
Photo Credit: Thor Swift/Berkeley Lab
Scientific Frontline: Extended "At a Glance" Summary: Huntington's Disease
The Core Concept: A fatal, inherited neurodegenerative condition linked to a mutated copy of a protein-coding gene that leads to the death of neurons in the brain, cognitive and physical decline, and death.
Key Distinction/Mechanism: While previously focused on mutational repeat expansion in the huntingtin gene, recent research identifies double-stranded DNA breaks (DSBs) as a distinct parallel pathway driving neurodegeneration, independent of the expansion itself. Mutant huntingtin protein suppresses the activity of DNA repair enzymes.
Major Frameworks/Components:
- Genetic Mutation: A mutated huntingtin gene containing extra repeating sequenc
es (CAG expansion). - Metabolic Shift: Support cells in the striatum reduce glucose uptake, switching to fatty acids, which generate tissue-damaging reactive oxygen species (ROS).
- DNA Damage: Accumulation of double-stranded DNA breaks (DSBs), primarily in the striatum's neurons, exacerbated by the mutant huntingtin protein suppressing DNA repair enzymes.
- Antioxidant Intervention: XJB-5-131, a synthetic antioxidant capable of crossing the blood-brain barrier to target mitochondria and neutralize ROS.
Branch of Science: Genetics, Neurobiology, and Biochemistry.
Future Application: Antioxidant therapy (such as XJB-5-131) could potentially be developed to halt neurodegeneration in human patients, possibly in conjunction with gene-modifying therapies to target the disease at its root.
Why It Matters: This discovery shifts focus toward a new, potentially simpler therapeutic strategy using investigational antioxidants to address the DNA damage driving symptom onset, providing hope for an incurable disease where complicated genetic interventions have previously failed.
New treatments for Huntington’s disease could soon be on the horizon, following research led by scientists at Lawrence Berkeley National Laboratory (Berkeley Lab).
Huntington’s disease (HD) is a fatal, inherited neurodegenerative condition. People with HD have a mutated copy of a protein-coding gene that contains many extra nucleotides in a repeating sequence. The exact functions of this protein, called huntingtin, are unknown. In individuals with the HD mutation, however, neurons in certain regions of the brain begin to die in adulthood, leading to cognitive and physical decline and, eventually, death. Previous research has revealed that over the course of a patient’s life, the mutated gene gains even more of these repeats due to errors that occur during cell division. The more repeats a person has, the earlier the disease onset and the more severe the symptoms. Until now, it was unclear how the mutation, the subsequent mutant protein, and the ongoing mutational repeat expansion over a patient’s lifetime led to neurodegeneration.
The team’s study, published in Nature Communications, revealed that an additional, previously overlooked characteristic of HD appears to be driving the neurodegeneration—a marked increase in breaks in DNA strands across the genome. The researchers then demonstrated that treatment with an antioxidant suppresses these breaks and rescues mice from neuron damage and symptoms of the disease.
“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 and research scientist in Berkeley Lab’s Biosciences Area. “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 co-led the work alongside senior lead Cynthia McMurray, a retiree affiliate in the Biosciences Area. McMurray has spent decades studying the genetic and cellular changes underlying HD, first at the Mayo Clinic and then at Berkeley Lab.
“I believe we’re opening the door to a new way to treat Huntington’s patients,” said McMurray. “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. Past approaches have tried to edit the gene, shorten the repeats, or block the gene’s expression; those are complicated interventions, and none of them have translated into efficacy for real patients. The question is, will ours work in humans? The next step is to show that our findings apply to human cells and that we can protect neurons, which would be a precursor leading to clinical trials.”
.jpg)
This super-resolution fluorescence microscopy image shows tissue from the striatum region of the brain from a HD mouse model. The red spots indicate the presence of broken DNA strands, which leads to the hallmark symptoms of HD and eventually death.
Image Credit: Aris Polyzos/Berkeley Lab
.jpg)
This super-resolution fluorescence microscopy image shows the nucleus of a neuron in the striatum region of the brain from a HD mouse model. The red spots indicate the presence of broken DNA strands, which leads to the hallmark symptoms of HD and eventually death.
Image Credit: Aris Polyzos/Berkeley Lab
New Insights from Cell Studies
McMurray and Polyzos, along with colleagues from Berkeley Lab and the Harvard T.H. Chan School of Public Health, began studying energy uptake in HD neurons ten years ago, after research by others showed that metabolic changes occur in the brains of patients with HD before symptoms begin. Using a mouse model of the disease, the team saw that the support cells for neurons in the striatum, the brain region most severely affected by HD, reduced their uptake of glucose—the standard fuel for the brain—and switched instead to using fatty acids to generate ATP for themselves and their dependent neurons. Mice have the same huntingtin gene as humans. When edited to contain the hallmark mutation of HD, this gene also leads to a late-onset neurodegenerative condition in the animals. When mitochondria inside cells break down fatty molecules for fuel, byproducts called reactive oxygen species (ROS) are generated. ROS are hazardous to cells and tissues because they are highly reactive and attach to most biomolecules. They are known to be particularly destructive to DNA, as oxidized DNA interferes with gene function and can lead to the breakage of DNA strands. Therefore, the team started looking at the integrity of the genomes in these cells.
They discovered a surprising accumulation of double-stranded DNA breaks (DSBs). These are the most severe type of breakage, in which the DNA double helix is broken. DSBs appear in cells throughout the body with age, but in HD, they accumulate significantly in neurons of the striatum. The continual damage causes cell dysfunction and death, giving rise to disease symptoms and the death of the individual before other areas of the brain are deeply affected.
Organisms across the tree of life have evolved cellular processes to mediate damage to DNA caused by ROS, UV exposure, and toxins. The discovery of excessive DSBs meant that something interferes with these safeguards in people with HD. The team later found that the normal huntingtin protein binds to DNA repair enzymes that fix these breaks. The protein’s role in healthy DNA repair remains unknown, but when the mutant huntingtin interacts with these enzymes, their activity is suppressed. The team believes this aspect of the disease was not discovered by earlier investigations because suppression is much harder to detect in genome studies than complete inhibition.
The researchers also discovered that the suppression of DSB repair is separate from the central CAG expansion in somatic cells (all the cells in the body except reproductive cells, such as eggs and sperm) that occurs with age. This discovery was key, as it illustrated that the disease unfolds on two parallel paths—and scientists working on drug research and development had only been targeting the mutation pathway.
“We clearly saw the repeats could expand unchecked during life, but it did not necessarily give rise to neuronal death,” said McMurray. In the Nature Communications paper, she and her colleagues engineered two lineages of mice with the HD gene: in one, the expansion proceeded normally during the mouse’s lifespan; in the other, the expansion was artificially blocked. Both groups of mice developed DSBs in their striatum, experienced symptoms, and died of the disease. “We connected the dots to show this is a two-stage process. The mutation is the driver of the disease because it generates a faulty protein, which is suppressing the ability to repair DSBs. But the huntingtin protein itself doesn’t kill cells.”
Armed with this key breakthrough, the team began tests with a synthetic antioxidant compound designed to mitigate ROS from mitochondria.
The purpose of antioxidants is to safely neutralize ROS to prevent cellular damage, but very few natural or synthetic antioxidants can cross the blood-brain barrier to reach neuron support cells. Peter Wipf, a distinguished professor of chemistry, pharmaceutical sciences, and bioengineering at the University of Pittsburgh, recently developed a compound called XJB-5-131 that is able to enter the brain and concentrate at mitochondria. “We realized that this compound might be what we’re looking for, a tool to delineate the role of DSBs in Huntington’s disease progression,” said McMurray.
She and Polyzos gave XJB-5-131, administered as a daily infusion, to mice with HD and were shocked by the efficacy.
The mice showed a reduction in double-stranded breaks, a lack of motor function deficits, and reduced inflammation in the brain.
“It basically attenuated the disease,” said McMurray.
Next Steps
The promising results of this study have already garnered enthusiasm from other HD researchers. Scientists around the world are now curious to see what happens when antioxidants are administered to human patients. The first step is to establish that the same disease mechanism that was curable in mice also occurs in humans. Polyzos is leading a study using induced pluripotent stem cells taken from patients with HD, which will be coaxed to differentiate into neurons. The team can use these to confirm that the disease-induced DNA breakage results in neuronal death in a human context, and to further investigate how the disease suppresses DNA repair.
Polyzos and McMurray are optimistic that the results will translate, as the cellular processes involved are known to be identical across species.
Despite the breakthrough proof of concept, it is unclear whether antioxidant therapy alone will be sufficient for a long-term treatment of the disease in humans, as it does not deal with the mutated protein itself. Polyzos speculates that in the future, a cure that allows genetic carriers to have a normal life expectancy without symptoms might involve a compound like XJB-5-131 to prevent double-stranded breaks, alongside a gene-modifying therapy to fix the mutation at the root of the disease.
Funding: This research project is supported by the National Institutes of Health.
Published in journal: Nature Communications
Authors: Aris A. Polyzos, Ana Cheong, Jung Hyun Yoo, Lana Blagec, Zachary D. Nagel, and Cynthia T. McMurray
Source/Credit: Lawrence Berkeley National Laboratory | Aliyah Kovner
Edited by: Scientific Frontline
Reference Number: gen081726_02
