Huntington’s Disease, a debilitating genetic disorder that affects the brain, has long puzzled scientists and clinicians alike. Patients with this disease experience a gradual deterioration of nerve cells, leading to a host of physical and cognitive symptoms. However, recent research conducted by McMaster University has shed new light on the underlying mechanisms of this devastating condition.
In a groundbreaking study published in the Proceedings of the National Academy of Sciences on Sept. 27, 2024, researchers from McMaster University discovered that the protein mutated in patients with Huntington’s Disease plays a crucial role in DNA repair within brain cells. Specifically, the huntingtin protein is responsible for facilitating the production of Poly [ADP-ribose] (PAR) molecules, which are essential for the repair of damaged DNA.
The research team, led by McMaster research associate Tamara Maiuri, found that in individuals with Huntington’s Disease, the mutated version of the huntingtin protein is unable to stimulate PAR production effectively. As a result, DNA repair mechanisms are compromised, leading to increased DNA damage within brain cells. This discovery builds upon previous research conducted by McMaster’s Truant Lab in 2018, which first identified the huntingtin protein’s involvement in DNA repair processes.
Surprisingly, the study also revealed that levels of PAR were significantly lower in individuals with Huntington’s Disease, as well as in asymptomatic carriers of the disease gene. This finding contradicted previous research that had shown elevated PAR levels in patients with other neurodegenerative disorders, such as Parkinson’s and ALS. The implications of these findings are profound, as they highlight a previously unrecognized aspect of Huntington’s Disease pathology.
One of the most intriguing connections highlighted by this research is the potential link between Huntington’s Disease and cancer research. Ray Truant, senior author of the study and professor in McMaster’s Department of Biochemistry and Biomedical Sciences, pointed out that drugs known as PARP inhibitors, which suppress PAR production, are commonly used in cancer treatments. This observation raises the intriguing possibility that individuals carrying the Huntington’s Disease gene may have lower rates of cancer, potentially offering them an evolutionary advantage.
Building upon these findings, researchers at McMaster University are collaborating with Sheila Singh’s lab at the Centre for Discovery in Cancer Research to explore the therapeutic potential of huntingtin-level lowering drugs in cancer treatment. Further studies are also underway to investigate the efficacy of FDA-approved PARP1 inhibitor drugs in the treatment of neurodegenerative diseases beyond Huntington’s Disease.
This groundbreaking research was made possible through collaboration with University College London, Johns Hopkins University, and the University of Toronto. The state-of-the-art McMaster Center for Advanced Light Microscopy played a pivotal role in imaging the huntingtin protein with PAR chains, providing researchers with valuable insights into the molecular interactions underlying DNA repair processes.
Funding support for this research was provided by 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. These contributions underscore the importance of ongoing research initiatives aimed at unraveling the complexities of Huntington’s Disease and advancing our understanding of neurodegenerative disorders.
In conclusion, the findings of this study represent a significant milestone in Huntington’s Disease research, offering fresh insights into the molecular mechanisms underlying this devastating condition. By uncovering the role of the huntingtin protein in DNA repair processes, researchers have opened up new avenues for therapeutic intervention and potential crossover with cancer research. This research sets the stage for future studies that hold the promise of improving the lives of individuals affected by Huntington’s Disease and other neurodegenerative disorders.
