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Summary: Researchers at McMaster University found that the protein mutated in Huntington's Disease patients impairs DNA repair by impacting the production of PAR molecules responsible for DNA damage. This defect in the DNA repair mechanism leads to ineffective repair processes in brain cells, contributing to disease progression. The study builds upon previous research from McMaster's Truant Lab in 2018, highlighting the role of the huntingtin protein in DNA repair. Unexpectedly, lower PAR levels were observed in Huntington's Disease patients and carriers compared to other neurodegenerative disorders like Parkinson's and ALS.
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