McMaster researchers develop a new theory regarding Huntington’s Disease that may shape the future of drug development for the condition.
A team of researchers from the university found that a unique type of signalling found in damaged DNA signals huntingtin – a protein found mutated in the genes of those diagnosed with Huntington’s Disease – to aid in DNA repair is defective for those with the condition.
The new hypothesis was published in the Proceedings of the National Academy of Science (PNAS).
“The concept was that if we applied the signalling molecule back in excess, even orally, this signalling can be restored in the Huntington’s disease mouse brain,” says Laura Bowie, a PhD student in the Department of Biochemistry and Biomedical Sciences at McMaster. “The net result was that we fixed the modification of huntingtin not seen in mutant huntingtin in Huntington’s disease.”
Using this hypothesis, the study team discovered a molecule called N6-furfuryladenine, derived from the repair of DNA damage, which corrected the defect seen in mutant huntingtin.
“Based on dosing by different ways of this molecule in mouse Huntington’s disease models, Huntington’s disease symptoms were reversed,” says Bowie. “The mutant huntingtin protein levels were also restored to normal, which was a surprise to us.”
Ray Truant, senior author on the study, has dedicated his career to Huntington’s disease research and how mutation leads to Huntington’s disease. It was his lab that was the first to demonstrate that normal huntingtin was involved in DNA repair.
Truant argues that the traditional and controversial amyloid/protein misfolding hypothesis, where a group of proteins stick together forming brain deposits, is likely the result of the disease, rather than its cause.
He also stated that he considers this paper the most significant of his career.
“This is an important new lead and a new hypothesis, but it is important for people to know this is not a drug or cure,” says Truant, professor in the Department of Biochemistry and Biomedical Sciences at McMaster. “This is the first new hypothesis for Huntington’s disease in 25 years that does not rely on the version of the amyloid hypothesis which has consistently failed in drug development for other diseases.”
Huntington’s Disease is an inherited, neurodegenerative illness that comes with dire physical, cognitive and emotional symptoms that often hit around middle age. The mutant huntingtin protein causes certain parts of the brain to die – specifically the caudate, the putamen and, as the disease progresses, the cerebral cortex.
“Innovative research initiatives, such as the work led by the team in Dr. Truant’s lab, including PhD student Laurie Bowie, has the potential to transform HD research,” says Bev Heim-Myers, CEO of the Huntington Society of Canada. “The answers we find for Huntington’s disease will likely lead to better understanding of treatments for other neurological diseases and it is important that we continue this cross-talk amongst neurodegenerative diseases.”
The study was conducted in partnership with the University of Alberta, Western University, Johns Hopkins University, and a collaboration with a U.S. biotech firm, Mitokinin LLC. Their work now continues in developing better derivatives of N6-furfuryladenine towards developing a drug.
This study was funded by the Canadian Institutes of Health Research, the Krembil Foundation, and the Huntington Society of Canada.