The protein that mutates in patients with Huntington’s disease can’t repair DNA as intended, impacting the ability of brain cells to heal themselves, McMaster researchers have discovered.

The research, published Sept. 27, 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.

But in people with Huntington’s disease, 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 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 disease and Amyotrophic lateral sclerosis (ALS).

Huntington’s disease is a genetic disorder that affects the brain and causes the gradual deterioration of nerve cells. Children with a parent who has Huntington’s disease have a 50 per cent chance of inheriting the gene.

Future study on Huntington’s and cancer research

This discovery has a unique connection with cancer research: Drugs that stop PAR production — called PARP inhibitors — are used as cancer treatments, says Ray Truant, senior author of the study and a professor in the department of Biochemistry and Biomedical Sciences.

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 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,” Truant says.

“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.

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 say.

Researchers with University College London, Johns Hopkins University and the University of Toronto assisted with this study.

Researchers used the new McMaster Center for Advanced Light Microscopy for imaging of the huntingtin protein with PAR chains, to get a closer look at how these molecules interact.