Researchers have made a significant breakthrough in understanding Huntington’s disease. They discovered that the protein mutated in Huntington’s disease patients fails to repair DNA effectively, which affects the brain cells’ capacity for self-repair.
Researchers from McMaster University have made a crucial discovery regarding the mutated protein found in patients with Huntington’s Disease, revealing it does not repair DNA effectively, hindering the self-repair abilities of brain cells.
The findings, published on September 27, 2024, in the Proceedings of the National Academy of Sciences, indicate that the huntingtin protein plays a role in generating essential molecules for repairing DNA damage. These molecules, termed Poly [ADP-ribose] (PAR), surround damaged DNA and function like a net that captures the necessary components for the repair process.
However, in individuals with Huntington’s Disease, it was revealed that the mutated form of this protein does not work correctly and fails to stimulate the production of PAR, leading to less effective DNA repair. This research builds on earlier findings made by McMaster’s Truant Lab in 2018, which initially highlighted the involvement of the huntingtin protein in DNA repair.
“We examined PAR levels in the spinal fluid of Huntington’s Disease patients and anticipated they would be elevated due to increased DNA damage. Surprisingly, we found the opposite,” says lead author and McMaster research associate Tamara Maiuri. “The levels were actually quite lower not only in Huntington’s Disease patients but also in individuals who carry the gene without showing any visible symptoms yet.”
This revelation was unexpected, especially since prior studies indicated that PAR levels tend to be higher in patients with other neurodegenerative diseases like Parkinson’s and Amyotrophic lateral sclerosis (ALS).
Huntington’s Disease is a hereditary disorder that affects brain function, causing progressive deterioration of nerve cells. There is a 50 percent probability for children of parents with Huntington’s Disease to inherit the gene.
Future Research on Huntington’s Disease and Cancer
This finding intriguingly overlaps with cancer research. Ray Truant, the senior author of the study and a professor in McMaster’s Department of Biochemistry and Biomedical Sciences, notes that there are drugs known as PARP inhibitors that halt PAR production and are used in cancer treatment.
Truant explains that this may clarify why individuals who carry the Huntington’s Disease gene exhibit considerably lower cancer rates, suggesting a potential evolutionary advantage due to a reduced risk of cancer in early life.
“One potential takeaway is that new drugs aimed at reducing huntingtin levels, which are currently undergoing clinical trials, might also be beneficial for cancer. Based on the insights from this paper, we are collaborating with Sheila Singh’s lab at McMaster University’s Centre for Discovery in Cancer Research to explore this further,” Truant states.
Researchers suggest that future investigations should examine various classes of FDA-approved PARP1 inhibitors, as these could show promise not only for Huntington’s Disease but also for a range of neurodegenerative disorders.
The study also involved researchers from University College London, Johns Hopkins University, and the University of Toronto. The newly established McMaster Center for Advanced Light Microscopy was utilized to observe the huntingtin protein with PAR chains, providing researchers a detailed view of how these molecules interact. The imaging work was aided by McMaster’s Andres Lab.
This research received funding from the Canadian Institutes of Health Research Project Grant, the Krembil Foundation, the Huntington Disease Society of America Berman Topper Career Development Fellowship, and the HD Human Biology Project.
