Researchers discover what hinders DNA repair in Huntington’s disease patients

Researchers at McMaster University have discovered that the mutated protein in Huntington’s disease patients does not repair DNA as expected, impacting the ability of brain cells to heal themselves.

The research, published in PNAS on September 27, 2024, discovered that the huntingtin protein helps create special molecules important for repairing DNA damage. These molecules, known as Poly(ADP-ribose)(PAR), gather around damaged DNA and, like a net, attract all the factors necessary for the repair process.

In people with Huntington’s disease, however, research has found that the mutated version of this protein does not function properly and is not able to stimulate PAR production, which ultimately leads to DNA repair. less effective. The study builds on a finding published by researchers at McMaster’s Truant Lab in 2018, which for the first time detailed the involvement of the huntingtin protein in DNA repair.

“We looked at PAR levels in the cerebrospinal fluid of patients with Huntington’s disease and expected them to be higher due to higher levels of DNA damage, but we actually found the opposite,” says Tamara Maiuri, lead author and research associate at McMaster. “The levels were a little lower and not just in the Huntington’s disease samples, but also in people who carried the gene but were not yet showing outward symptoms.”

This is an unexpected finding, as researchers have previously found that PAR levels are elevated in patients with other neurodegenerative disorders like Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

Huntington’s disease is a genetic disorder that affects the brain and causes the progressive deterioration of nerve cells. For children whose parents have Huntington’s disease, there is a 50% chance that they will inherit the gene.

Future study on Huntington’s disease and cancer research

This discovery has a unique connection to cancer research. Ray Truant, lead author of the study and professor in 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 could explain a long-standing observation that carriers of the Huntington’s disease gene have significantly lower rates of cancer and could confer an evolutionary advantage to the human population, avoiding early cancer.

“One implication is that new huntingtin-lowering drugs already in clinical trials may have utility outside of Huntington’s disease for cancer. Based on the results of this paper, we are working in collaboration with the Sheila Singh’s lab at McMaster University’s Cancer Discovery Center research to further explore the potential,” says Truant.

The researchers say future studies should examine different classes of FDA-approved PARP1 inhibitor drugs because they may hold promise not only for Huntington’s disease, but also for neurodegenerative diseases in general.

Researchers from University College London, Johns Hopkins University and the University of Toronto participated in this study. The new McMaster Center for Advanced Optical Microscopy was also used to image the huntingtin protein with PAR chains, allowing researchers to take a closer look at how these molecules interact. This was done with the help of McMaster’s Andres Lab.