Scientists at the Brain Research Centre and Centre for Molecular Medicine and Therapeutics have uncovered a key cellular mechanism that alters brain cell function in Huntington's disease, and identified a possible treatment for the disease.
The results of the study were published online today and will appear in the January 28 edition of the journal Neuron.
Huntington's disease is an inherited degenerative brain disease that causes cognitive and motor impairment, and eventually death. One in 10,000 Canadians suffers from Huntington's disease.
The researchers found that, in mouse models, the genetic mutation that causes Huntington's disease results in an excessive number of NMDA receptors--special receptors found at the surface of brain cells--to accumulate and be active outside synapses, which are the connections between brain cells. In healthy conditions, there should be few NMDA receptors outside the synapse.
The researchers also found that the over-activation of the NMDA receptors outside the synapse leads to a reduction in brain cell survival signals and disruption in brain function.
"Previous work in cell cultures showed that NMDA receptors located within the synapse can have beneficial effects on brain cells, whereas NMDA receptors outside the synapse, called 'extra-synaptic NMDA receptors,' have a detrimental effect," says Dr. Lynn Raymond, a professor in the UBC Department of Psychiatry, a member of the Brain Research Centre at UBC Hospital, and co-director of the Huntington's Disease Medical Clinic.
"Our study shows an increase in the number of extrasynaptic NMDA receptors, shifting the balance between these opposing cellular mechanisms in animal models of early stages of Huntington's disease," Raymond says.
While further work still needs to be done to determine how the genetic mutation causes the excessive number and activity of NMDA receptors to localize outside the synapses, the researchers did find a way to mitigate damage and slow disease progression at early stages of the disease--using Memantine, a drug currently used to treat Alzheimer's disease.
"Memantine in low dose works by preferentially blocking the activity of NMDA receptors outside the synapse," says Dr. Michael Hayden, director of the Centre for Molecular Medicine and Therapeutics, professor in the UBC Department of Medical Genetics, and co-author on the study.
"It was previously shown to reverse deficits and damage in late stages of animal models of Huntington's disease, but we found it could improve learning and cell survival signaling even at early stages of the disease," says Hayden. "A small human clinical trial of Memantine for Huntington's disease has also recently shown positive effects. Larger, international clinical trials are now being planned."
"Memantine's beneficial effects appear to be dose-specific," Raymond adds. "Before it can be prescribed to treat Huntington's disease, we need to know how to determine appropriate dosing and whether it interferes with other essential cellular and brain functions."
This study was funded by the Canadian Institutes of Health Research, Cure Huntington Disease Initiative, Michael Smith Foundation for Health Research, Heart & Stroke Foundation of BC & Yukon, Huntington's Disease Society of America, and the Huntington Society of Canada.
The Brain Research Centre comprises more than 225 investigators with multidisciplinary expertise in neuroscience research ranging from the test tube, to the bedside, to industrial spin-offs. The Centre is a partnership of the UBC Faculty of Medicine and Vancouver Coastal Health Research Institute. www.brain.ubc.ca
The Centre for Molecular Medicine & Therapeutics (CMMT)
CMMT is a premier genetics science research centre in Canada and the world, dedicated to unravelling the many genetic questions surrounding human illness and well being. It is a unique collaboration of committed scientists and researchers, who participate in multidisciplinary teams with the optimal combination of expertise, to find new approaches to treatment and prevention that can overcome the causes of illness. Affiliated with the University of British Columbia and the Child & Family Research Institute, CMMT conducts discovery research and translates that research into novel and effective clinical and therapeutic strategies to promote health. For more information, visit: http://www.
The Child & Family Research Institute (CFRI) conducts discovery, clinical and applied research to benefit the health of children and families. It is the largest institute of its kind in Western Canada. CFRI works in close partnership with the University of British Columbia, BC Children's Hospital and Sunny Hill Health Centre for Children, BC Women's Hospital & Health Centre, agencies of the Provincial Health Services Authority, and BC Children's Hospital Foundation. CFRI has additional important relationships with BC's five regional health authorities and with BC academic institutions Simon Fraser University, the University of Victoria, the University of Northern British Columbia, and the British Columbia Institute of Technology. www.cfri.ca
The UBC Faculty of Medicine provides innovative programs in the health and life sciences, teaching students at the undergraduate, graduate and postgraduate levels, and generates more than $200 million in research funding each year. www.med.ubc.ca
Vancouver Coastal Health Research Institute (VCHRI) is the research body of Vancouver Coastal Health Authority, which includes BC's largest academic and teaching health sciences centres: VGH, UBC Hospital, and GF Strong Rehabilitation Centre. In academic partnership with the University of British Columbia, VCHRI brings innovation and discovery to patient care, advancing healthier lives in healthy communities across British Columbia, Canada, and beyond. www.vchri.ca