Scientists have identified how Huntington's disease (HD) is caused. The discovery is expected to offer new therapeutic potential for treating the disorder.
HD is a rare inherited neurological disorder that is estimated to affect about one in every 10,000 persons.
Ray Truant, professor in the Department of Biochemistry and Biomedical Sciences at McMaster University, has been studying the biological role of the Huntington protein and the sequences in the protein that tell it where to go within a brain cell.
"These are exciting results by the McMaster team," said Dr. Rémi Quirion, Scientific Director at the Canadian Institutes of Health Research, Institute of Neuroscience, Mental Health and Addiction.
"Even if the Huntington protein has been known for almost 20 years, the cause of Huntington's disease is still not clear. Data reported here shed new lights on this aspect and possibly leading to new therapeutic potential in the future," Dr. Quirion added.
The disorder results from degeneration of brain cells, that causes uncontrolled limb movements and loss of intellectual faculties, eventually leading to death. There is no treatment. HD is a familial disease, passed from parent to child through a mutation in the normal gene.
Truant and PhD candidate graduate student, Randy Singh Atwal, have discovered a small protein sequence in Huntington that allows it to locate to the part of the cell critical for protein quality control. Similar findings have been seen to be very important for other neuro-degenerative diseases such as Parkinson's and Alzheimer's diseases.
Huntington protein is essential for normal development in all mammals, and is found in all cells, yet its function was unknown. It appears that Huntington is crucial for a brain cell's response to stress, and moves from the endoplasmic reticulum into the nucleus, the control centre of the cell. When mutant Huntington is expressed however, it enters the nucleus as it should in response to stress, but it cannot exit properly, piling up in the nucleus and leading to brain cell death in HD.
"What is important to Huntington disease research is that in the learning of the basic cell biology of this protein, we have also uncovered a new drug target for the disease," said Atwal.
Atwal additionally found that Huntington can be sent to the nucleus by protein modifying enzymes called kinases, and he has determined the three-dimensional shape of this sequence.
Truant and Atwal's work indicates that if mutant Huntington is prevented from entering the nucleus, it cannot kill a brain cell. This means that a kinase inhibitor drug may be effective for Huntington's disease. Kinase inhibitors form the largest number of successful new generation drugs that are coming to market for a plethora of diseases including stroke, arthritis and cancer.
"This is most exciting to us, because we immediately have all the tools and support in hand at McMaster to quickly hunt this kinase down, and find potential new drugs for Huntington's disease in ways that are similar or better than a large pharmaceutical company", said Truant.
"We can actually watch Huntington protein move inside of a single live brain cell in real time in response to stress, and we can watch mutant Huntington kill that cell, even over days."
"Using molecular tools, computer software and sophisticated laser microscopy techniques which we've been developing at McMaster over the last seven years, researchers can now use these methods to hopefully watch a drug stop this from happening."
Truant's laboratory is supported by grants from the United States High Q Foundation, the Canadian Institutes of Health Research, the Huntington Society of Canada and the Canada Foundation for Innovation.
"This discovery reflects Dr. Truant's growing contribution to the international campaign to create a world free from Huntington disease," said Don Lamont, CEO and Executive Director of the Huntington Society of Canada - Canada's only organization focused on research, education and support in the HD field.
"Our families live on a 'tightrope' waiting for an effective treatment or a cure for HD. The discovery provides hope for the Huntington community - most of all, hope that their children will not have to suffer the devastation of this inherited disease," said Lamont.