Cure found for Huntington disease in mice offers hope for treatment in humans

June 16, 2006

VANCOUVER, B.C.: Researchers at the University of British Columbia's Centre for Molecular Medicine and Therapeutics (CMMT) have provided ground-breaking evidence for a cure for Huntington disease in a mouse offering hope that this disease can be relieved in humans.

Published today in Cell journal, Dr. Michael Hayden and colleagues discovered that by preventing the cleavage of the mutant huntingtin protein responsible for Huntington disease (HD) in a mouse model, the degenerative symptoms underlying the illness do not appear and the mouse displays normal brain function. This is the first time that a cure for HD in mice has been successfully achieved.

"Ten years ago, we discovered that huntingtin is cleaved by 'molecular scissors' which led to the hypothesis that cleavage of huntingtin may play a key role in causing Huntington disease", said Dr. Michael Hayden, Director and Senior Scientist at the Child and Family Research Institute's Centre for Molecular Medicine and Therapeutics. Dr. Hayden is also a Canada Research Chair in Human Genetics and Molecular Medicine.

Now a decade later, this hypothesis has resulted in a landmark discovery. "This is a monumental effort that provides the most compelling evidence of this hypothesis to date", said Dr. Marian DiFiglia, Professor in Neurology, Massachusetts General Hospital, Harvard Medical School and one of the world's leading experts on Huntington disease. "Dr. Hayden and his team have shown in convincing fashion that many of the changes seen in HD patients can be erased in HD mice simply by engineering a mutation into the disease gene that prevents the protein from getting cleaved at a specific site".

To explore the role of cleavage, Dr. Hayden's team established an animal model of HD that replicated the key disease features seen in patients. A unique aspect of this particular animal model is that it embodied the human HD gene in exactly the same way seen in patients. This replication allowed researchers to examine the progression of HD symptoms including the inevitable cleavage of the mutant huntingtin protein. In the study, researchers confirmed that the deadly cleavage is caused by a key enzyme called caspase-6. By blocking the action of this target, they showed that the mouse did not develop any symptoms of Huntington disease.

Hayden's team is now trying to test this model of prevention in a mouse using drug inhibitors and then ultimately in humans. "Our findings are important because they tell us exactly what we need to do next", said Dr. Rona Graham, Post Doctoral Fellow at the CMMT and lead author in the study.

This work is also pivotal for the individuals and families affected by Huntington disease. "Patients of this disease should know that this is a research milestone for all and that this work brings the field closer to finding effective treatment for a devastating disorder", said Dr. DiFiglia.

The Huntington Society of Canada (HSC), a national network of volunteers and professionals united in the fight against HD, echoed this sentiment. "This ground-breaking research provides great hope for the Huntington community", said Don Lamont, the Society's CEO and Executive Director. "This research brings us closer to treatment and ultimately a cure".

Huntington disease is a degenerative brain disease that affects one in every 10,000 Canadians. One in 1,000 is touched by HD -- for example, as a person with HD, a family member, a person at risk, caregiver or friend. The disease results from degeneration of neurons in certain areas of the brain causing uncontrolled movements, loss of intellectual faculties, and emotional disturbances. Currently, there is no treatment to delay or prevent HD in patients.
-end-
This research was funded by Canadian Institutes of Health Research, Hereditary Disease Foundation, Huntington Disease Society of America, Michael Smith Foundation for Health Research, High Q Foundation, Merck Frosst, Child and Family Research Institute of BC.

To request an interview with Dr. Michael Hayden or members of his team, please contact:

Alexandra Howard, Communications
Centre for Molecular Medicine and Therapeutics (CMMT)
T: 604.875.3881
E: alexandra@cmmt.ubc.ca

Hilary Thomson, UBC Public Affairs
University of British Columbia
T: 604 822 2644
E: hilary.thomson@ubc.ca
www.cmmt.ubc.ca

Journal Reference:
Title: Cleavage at the Caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin
Author(s): Rona K. Graham, Yu Deng, Elizabeth J. Slow, Brendan Haigh, Nagat Bissada, Ge Lu, Jacqueline Pearson, Jacqueline Shehadeh, Lisa Bertram, Zoe Murphy, Simon C. Warby, Crystal N. Doty, Sophie Roy, Cheryl L. Wellington, Blair R. Leavitt, Lynn A. Raymond, Donald W. Nicholson and Michael R. Hayden
Source: Cell 125, 1179-1191, June 16 2006

The Centre for Molecular Medicine and Therapeutics (CMMT): The centre for Molecular Medicine and Therapeutics at the BC Children's Hospital is a research centre supported collaboratively by the University of British Columbia, the Child and Family Research Institute, Merck Frosst Canada Inc., and the Government of British Columbia. Built on a 10-year history of research excellence, the CMMT is dedicated to advancing the fundamental understanding of the molecular function and structure of genes as the key to improved diagnosis, treatment and prevention of health problems in children and adults. For more information, please refer to the website at www.cmmt.ubc.ca.

University of British Columbia

Related Protein Articles from Brightsurf:

The protein dress of a neuron
New method marks proteins and reveals the receptors in which neurons are dressed

Memory protein
When UC Santa Barbara materials scientist Omar Saleh and graduate student Ian Morgan sought to understand the mechanical behaviors of disordered proteins in the lab, they expected that after being stretched, one particular model protein would snap back instantaneously, like a rubber band.

Diets high in protein, particularly plant protein, linked to lower risk of death
Diets high in protein, particularly plant protein, are associated with a lower risk of death from any cause, finds an analysis of the latest evidence published by The BMJ today.

A new understanding of protein movement
A team of UD engineers has uncovered the role of surface diffusion in protein transport, which could aid biopharmaceutical processing.

A new biotinylation enzyme for analyzing protein-protein interactions
Proteins play roles by interacting with various other proteins. Therefore, interaction analysis is an indispensable technique for studying the function of proteins.

Substituting the next-best protein
Children born with Duchenne muscular dystrophy have a mutation in the X-chromosome gene that would normally code for dystrophin, a protein that provides structural integrity to skeletal muscles.

A direct protein-to-protein binding couples cell survival to cell proliferation
The regulators of apoptosis watch over cell replication and the decision to enter the cell cycle.

A protein that controls inflammation
A study by the research team of Prof. Geert van Loo (VIB-UGent Center for Inflammation Research) has unraveled a critical molecular mechanism behind autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis.

Resurrecting ancient protein partners reveals origin of protein regulation
After reconstructing the ancient forms of two cellular proteins, scientists discovered the earliest known instance of a complex form of protein regulation.

Sensing protein wellbeing
The folding state of the proteins in live cells often reflect the cell's general health.

Read More: Protein News and Protein Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.