Summary: Researchers have discovered that the protein mutated in Huntington’s Disease fails to properly repair DNA, leading to reduced brain cell healing. The huntingtin protein normally stimulates the production of PAR molecules, which gather around damaged DNA to facilitate repair.
In Huntington’s patients, the mutated protein does not trigger this process effectively, leading to less efficient DNA repair. This finding could also explain why Huntington’s carriers have lower cancer rates, and it opens new avenues for using PARP inhibitors, typically used in cancer treatment, to explore potential therapies.
Key Facts:
- Mutated huntingtin protein fails to stimulate DNA repair, leading to brain damage.
- Huntington’s carriers show lower rates of cancer, possibly due to this mutation.
- Future research may explore using PARP inhibitors as therapies for neurodegenerative diseases.
Source: McMaster University
Researchers with McMaster University have discovered that the protein mutated in patients with Huntington’s Disease doesn’t repair DNA as intended, impacting the ability of brain cells to heal themselves.
The research, published in PNAS on Sept. 27, 2024, found that the huntingtin protein helps create special molecules that are important for fixing DNA damage. These molecules, known as Poly [ADP-ribose] (PAR), gather around damaged DNA and, like a net, pull in all the factors needed for the repair process.
In people with Huntington’s Disease, however, the research found that the mutated version of this protein doesn’t function properly and isn’t capable of stimulating PAR production, ultimately resulting in less effective DNA repair.
The study builds off a discovery researchers with McMaster’s Truant Lab published in 2018, which first detailed the huntingtin protein’s involvement in DNA repair.
“We looked at the PAR levels in the spinal fluid from Huntington’s Disease patients and expected it would be higher due to the higher levels of DNA damage, but we actually found the opposite,” says lead author and McMaster research associate Tamara Maiuri.
“The levels were quite a bit lower and not only in Huntington’s Disease samples, but also in people who carry the gene but aren’t yet showing outward symptoms.”
This was an unexpected discovery because researchers have previously found PAR levels to be elevated in patients with other neurodegenerative disorders like Parkinson’s and Amyotrophic lateral sclerosis (ALS).
Huntington’s Disease is a genetic disorder that affects the brain and causes the gradual deterioration of nerve cells. For children of parents who have Huntington’s Disease, there’s a 50 per cent chance they will inherit the gene.
Future study on Huntington’s and cancer research
This discovery has a unique connection with cancer research. Ray Truant, senior author of the study and professor with McMaster’s Department of Biochemistry and Biomedical Sciences, says there are drugs that stop PAR production called PARP inhibitors that are used as cancer treatments.
Truant says this may explain a long-standing observation that carriers of the Huntington’s Disease gene have significantly lower rates of cancer and may confer an evolutionary advantage in the human population, by avoiding early life cancer.
“One implication is that new huntingtin-level lowering drugs already in clinical trials may have utility outside of Huntington’s Disease to cancer. Based off the findings in this paper, we are working in collaboration with Sheila Singh’s lab at McMaster University’s Centre for Discovery in Cancer Research to investigate the potential further,” Truant says.
Researchers say future studies should look at different classes of FDA-approved PARP1 inhibitor drugs as they may hold promise not just for Huntington’s Disease but neurodegenerative diseases at large.
Researchers with University College London, Johns Hopkins University and the University of Toronto assisted with this study. The new McMaster Center for Advanced Light Microscopy was also utilized to image the huntingtin protein with PAR chains, giving researchers a closer look at how these molecules interact. This was done with the assistance of McMaster’s Andres Lab.
Funding: This research was supported by the Canadian Institutes of Health Research Project Grant and the Krembil Foundation, the Huntington Disease Society of America Berman Topper Career Development Fellowship and HD Human Biology Project.
About this genetics and Huntington’s disease research news
Author: Jennifer Stranges
Source: McMaster University
Contact: Jennifer Stranges – McMaster University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Poly ADP-ribose signaling is dysregulated in Huntington disease” by Tamara Maiuri et al. PNAS
Abstract
Poly ADP-ribose signaling is dysregulated in Huntington disease
Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract in the HTT protein.
Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways.
Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly adenosine diphosphate (ADP)-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia.
We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD induced pluripotent stem cell-derived neurons and patient-derived fibroblasts have diminished PAR response in the context of elevated DNA damage.
We have defined a PAR-binding motif in HTT, detected HTT complexed with PARylated proteins in human cells during stress, and localized HTT to mitotic chromosomes upon inhibition of PAR degradation. Direct HTT PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level.
While wild-type and mutant HTT did not differ in their PAR binding ability, purified wild-type HTT protein increased in vitro PARP1 activity while mutant HTT did not.
These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies.
