Huntingtin Protein Dysfunction Impairs DNA Repair in Huntington Disease

Researchers at McMaster University have discovered that a mutated form of the huntingtin protein in Huntington disease (HD) patients impairs the DNA repair process, affecting the brain cells' ability to heal. This new insight provides potential avenues for both HD and cancer treatments.

Key Findings on the Role of Huntingtin Protein

The study, published in PNAS, shows that the huntingtin protein helps create Poly [ADP-ribose] (PAR), molecules crucial for DNA damage repair. In healthy individuals, PAR acts like a net, gathering the necessary factors to fix damaged DNA.

• Impaired Function in HD: The mutated huntingtin protein in HD patients fails to stimulate adequate PAR production, leading to inefficient DNA repair.
• Comparison with Other Disorders: Unlike in disorders such as Parkinson's and ALS, where PAR levels are elevated, HD patients exhibited significantly lower PAR levels, even among gene carriers not yet showing symptoms.

"We looked at the PAR levels in the spinal fluid from Huntington disease patients and expected it would be higher due to the DNA damage, but we actually found the opposite," said Dr. Tamara Maiuri, lead author and research associate at McMaster.

Clinical Implications and Connection to Cancer Research

Interestingly, the study reveals a potential link between HD and cancer, as PARP inhibitors—drugs that inhibit PAR production—are commonly used in cancer treatment.

"Carriers of the Huntington disease gene have significantly lower rates of cancer," explains Dr. Ray Truant, senior author.
This phenomenon may offer an evolutionary advantage by potentially reducing the risk of early life cancers.

Future Directions:
The research team proposes that huntingtin-lowering drugs currently in clinical trials for HD might be investigated for their utility in cancer treatment. Ongoing collaboration with McMaster’s Center for Discovery in Cancer Research aims to explore these possibilities further.

Methodology and Collaborators

The research utilized advanced light microscopy to image huntingtin proteins alongside PAR chains, providing detailed insights into their interactions. The study involved multiple institutions, including University College London, Johns Hopkins University, and University of Toronto.

Future Research and Implications for Neurodegenerative Disorders

The study suggests future research into FDA-approved PARP1 inhibitors as possible treatment options for HD and other neurodegenerative diseases. Understanding the biological mechanisms behind the mutated huntingtin protein's role in DNA repair could lead to novel therapeutic approaches.

"The implications of this study extend beyond Huntington disease to cancer and possibly other neurodegenerative disorders," says Dr. Truant.

Reference

Journal Information: Proceedings of the National Academy of Sciences
Provided by: McMaster University