A drug used to treat Alzheimer’s disease may help harness the protective pathways of brain cells to stay the deadly symptoms of Huntington’s disease, according to new research.
Nearly two decades ago, scientists identified the cause of Huntington’s: a single mutant gene that produces a defective version of a protein known as huntingtin [see story, “We Found the Gene!”]. Since then, research on potential cures has been slow, and there is still no satisfactory treatment. One obstacle, scientists have discovered, is that the relationship between huntingtin and molecular signaling pathways in the brain is far more complex than expected.
The new research, by scientists at the University of California San Diego, the Burnham Institute for Medical Research, and the University of British Columbia’s Centre for Molecular Medicine and Therapeutics, suggests a new way to approach this problem.
Location matters for neural degeneration
Huntingtin is expressed throughout the body but is found in especially large concentrations in the brain. Scientists have worked to unravel the molecular underpinnings of the misfolded version of the protein for years [see also 2009 story, “Research Offers a Clue to Huntington’s”]. One area of recent interest has been a specific receptor, the N-methyl-D-aspartic acid (NMDA) glutamate receptor, which, paradoxically, seems to be involved in both the protection and breakdown of brain cells.
“There’s a kind of dichotomy that is quite interesting in this receptor,” says Giles Hardingham, a researcher at the University of Edinburgh’s Centre for Integrative Physiology. “The calcium flux through the receptor controls both neuroprotective pathways as well as the neurodegenerative ones.”
Hardingham and his colleagues discovered that where the NMDA receptor is located determines whether it is ushering in a cell’s protection or its demise. “We found NMDA receptors located in the synapse promote neuroprotection, while chronic activation of extra-synaptic locations promotes neuronal death,” he says.
Other researchers have found that excessive extra-synaptic activity increases the toxic effects seen in many neurodegenerative disorders, including those of mutant huntingtin. Conversely, normal synaptic transmission mitigates its harmful effects by causing the protein to clump, which renders it harmless.
This means that simply blocking all NMDA receptors wouldn’t work as therapy; any treatment must block the overexcited receptors outside the synapse but leave the health-promoting receptors inside the synapses alone.
Selective blocking of the NMDA receptor
A group led by the University of California, San Diego’s Stuart Lipton and the University of British Columbia’s Michael Hayden published a study in the Nov. 15, 2009, issue of Nature Medicine demonstrating just that: an FDA-approved Alzheimer’s drug, memantine, is able to selectively block only extra-synaptic NMDA receptors. This blocking promotes neuroprotection in both human nerve-cell cultures and in a mouse model of Huntington’s disease.
“This drug is what we call an uncompetitive inhibition, fast off-rate drug—it only interacts with the receptor when it is excessively activated,” Lipton says. “It’s a bit like a volume control. When the volume is too loud, or when there’s too much glutamate and the neuron is getting overexcited, memantine works as a control to turn that excitability back down towards normal.”
The researchers showed that low doses of the drug turned down the extra-synaptic excitability seen in Huntington’s but allowed normal synaptic transmission to continue—effectively promoting neuroprotective pathways over neurodegenerative ones.
But the dose is critical. “The authors showed that low-dose memantine increased aggregates and protected against striatal atrophy whereas a higher dose reduced aggregates and increased it,” says M. Flint Beal, a neuroscientist specializing in neurodegenerative disease at the Weill Medical College of Cornell University and a member of the Dana Alliance for Brain Initiatives. “This work fits nicely with many observations made previously and provides further evidence that excitotoxicity plays a role in Huntington’s pathogenesis.”
A potential target for other diseases
So far, treatments for Huntington’s remain limited to treating the symptoms, which begin with clumsiness, progress to jerky, uncontrollable movements consistent neuronal loss, and end in early death.
“Right now we can only treat the disease symptomatically,” Hayden says. “A patient has symptoms, maybe problems with movement or some kind of psychiatric disturbance, and we treat them piecemeal. There is nothing to change the course of the illness—to halt it or even just slow it down.”
Memantine may offer new promise for a more effective Huntington’s treatment or even a cure. Between the Nature Medicine study and promising data from small trials, Hayden and Lipton say they are building a case for setting up a large clinical trial of the drug.
Meanwhile, the new insights into the NMDA receptor’s dual roles might help scientists develop tests and treatments for other neurodegenerative disorders.
“NMDA receptors could represent a common target. It’s likely that what helps us in Huntington’s can also help us with other diseases,” Hayden says.
“It’s hard to predict who gets Alzheimer’s but it’s easy to predict who gets Huntington’s disease with a simple blood test. And a target like the NMDA receptor may offer us an opportunity to turn predictive medicine in Huntington’s into preventive medicine for other neurodegenerative diseases.”