By EurekAlert
Sunday, November 15, 2009
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VIDEO: Dr. Stuart Lipton describes his Nov. 15, 2009,
paper in Nature Medicine, in which he and colleagues show
how synaptic activity protects the brain from the misfolded
proteins that characterize...
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Investigators at Burnham Institute for Medical Research
(Burnham), the University of British Columbia's Centre for
Molecular Medicine and Therapeutics and the University of
California, San Diego have found that normal synaptic activity in
nerve cells (the electrical activity in the brain that allows nerve
cells to communicate with one another) protects the brain from the
misfolded proteins associated with Huntington's disease. In
contrast, excessive extrasynaptic activity (aberrant electrical
activity in the brain, usually not associated with communication
between nerve cells) enhances the misfolded proteins' deadly
effects. Researchers also found that the drug Memantine, which is
approved to treat Alzheimer's disease, successfully treated
Huntington's disease in a mouse model by preserving normal synaptic
electrical activity and suppressing excessive extrasynaptic
electrical activity. The research was published in the journal
Nature Medicine on November 15.
Huntington's disease is a hereditary condition caused by a
mutated huntingtin gene that creates a misfolded, and therefore
dysfunctional, protein. The new research shows that normal synaptic
receptor activity makes nerve cells more resistant to the mutant
proteins. However, excessive extrasynaptic activity contributed to
increased nerve cell death. The research team found that low doses
of Memantine reduce extrasynaptic activity without impairing
protective synaptic activity. The work was led by Stuart A. Lipton,
M.D., Ph.D., director of the Del E. Webb Center for Neuroscience,
Aging and Stem Cell Research at Burnham and professor in the
department of Neurosciences and attending neurologist at the
University of California, San Diego and Michael R. Hayden, M.D.,
Ph.D., University Killam professor in the department of Medical
Genetics at UBC and director of the Centre for Molecular Medicine
and Therapeutics at the Child & Family Research Institute.
"Chronic neurodegenerative diseases like Huntington's,
Alzheimer's and Parkinson's are all related to protein misfolding,"
said Dr. Lipton. "We show here, for the first time, that electrical
activity controls protein folding, and if you have a drug that can
adjust the electrical activity to the correct levels, you can
protect against misfolding. Also, this verifies that appropriate
electrical activity is protective, supporting the 'use it or lose
it theory' of brain activity at the molecular level. For example,
this finding may explain why epidemiologists have found that
'using' your brain by performing crossword puzzles and other games
can stave off cognitive decline in diseases like Alzheimer's."
In the new study, researchers initially tested nerve cell
cultures transfected with mutant Huntingtin protein and found that
reducing excessive NMDA-type glutamate receptor activity with
Memantine and other antagonists protected the nerve cells
(glutamate receptors are the main trigger of excitatory electrical
activity in the brain but in excess can cause nerve cell death, a
process called excitotoxicity). They also found that normal
synaptic activity was protective. Subsequently, they treated
Huntington's disease model mice with both high and low doses of
Memantine and found that the low doses were protective by blocking
pathological extrasynaptic activity, while high-dose Memantine
encouraged disease progression because it also blocked the
protective synaptic NMDA receptor activity.
"For a long time it's been known that excitotoxicity is an early
marker of Huntington's disease," said Dr. Hayden. "However, now we
have dissected the mechanism by which this happens, particularly
focusing on NMDA receptors outside the synapse. This creates novel
therapeutic opportunities to modulate these receptors with
potential protective effects on nerve cells."
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.
Dr. Lipton is the named inventor on worldwide patents for the
use of Memantine (marketed in the USA under the name Namenda®)
in neurodegenerative disorders, including Alzheimer's and
Huntington's disease. He is credited with the groundbreaking
discovery more than ten years ago of how Memantine works in the
brain and for spearheading early human clinical trials with the
drug.
SOURCE