A clutch of root-cause mechanisms responsible for Huntington’s disease (HD) an impenetrable, inherited, neurodegenerative ailment converge in the March 14, 2002, issue of the journal Neuron.

HD strikes its victims in the prime of middle age, well after they have borne children who may perpetuate the malady. Its hallmarks include jerky, dance-like staggering, facial twitching, onset at 30 to 40 years of age, and dementia leading inevitably to death in 10 to 20 years after diagnosis. It takes only a single mutation in the huntingtin gene that encodes the defective huntintin protein (htt), to kill the striatal brain cells that inflict HD (See BioWorld Today, March 23, 2001, p. 1.)

The paper in Neuron is titled: “Increased sensitivity to N-Methyl-D-Aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease.” Its senior author is research and clinical neurologist Lynn Raymond, a faculty member in the department of psychiatry at the University of British Columbia in Vancouver.

“Our principal finding,” Raymond told BioWorld Today, “is that NMDA has a type of receptor that responds to glutamate the predominant chemical transmitter in the brain. Glutamate excites cells in the brain in order to perform, so that we can have normal motor-neuron programming, process sensory information, lay down new memories things like that. If the receptors particularly a subtype of the glutamate receptor called NMDA-R become over-activated, then it can kill cerebral neurons because the over-excited cell shows up with excess calcium. Our results are significant in that they provide evidence that excitotoxicity may be relevant to HD.

“That’s sort of the background,” Raymond continued. “There has been some interest over the past 25 years for that type of glutamate receptor being over-activated and causing cell death in HD. We can mimic the type of neuronal vulnerability that is seen in HD brains by injecting drugs that activate these receptors into rodent and primate models.”

Molecular geneticist Michael Hayden, a co-author of the Neuron article, is creator of a transgenic mouse model that mimics Huntington’s disease symptomatically and cerebrally, from birth to death. He and Raymond collaborated to tackle the question: What happens to NMDA receptors when this mutant form of HD is present?

Scoping Mutant Role In Receptors

“The answer, we found,” Raymond said, “was that the activity of the NMDA receptor is increased, and that cells in the brains of the mouse model are more sensitive to over-activation of the receptor. More animals die. This was something that happened over time, because of stress to the cells due to other things. It seemed to be a primary change mediated by this mutant protein being present in huntingtin. It could subject the cells to chronic stress throughout life, which neurons can compensate for until they get to a point where they become overwhelmed as in HD progression.

“That can happen at different points in time,” Raymond noted. “As we age, the powerhouse of the cells, the mitochondria, accumulate mutations that don’t allow them to compensate for the calcium that the over-excited NMDA receptors bring into the cells.

“Our other important finding,” Raymond went on, “was that it wasn’t just an NMDA-type receptor, but a specific subtype within that group that has a distinct distribution in the brain. And therefore, if we can use inhibitors specific for that subtype rather than inhibiting all NMDA brain receptors, which are involved in normal functioning of the brain if we can just down-regulate that specific subtype, we’d probably have fewer side effects and be more effective in slowing progression of the disease. Finally, the fact that this abnormality is present from birth suggests that treating patients who have been identified as carrying the HD gene before they’re symptomatic might be quite important.”

She and her co-authors scrutinized the Hayden HD mouse model from three different perspectives.

“Our collaborators in Sweden injected a drug that would activate the NMDA receptor right into the striatum a part of the brain that normally degenerates in HD,” Raymond said. “They saw that there was a bigger loss of neurons in the HD mouse compared to their wild-type littermates. That is, they were more sensitive in vivo.

“My lab did the in vitro experiments,” Raymond continued. “We cultured the striatal neurons that were selectively vulnerable to HD, then treated them with NMDA. These neurons were coming from newly born neonatal mice. And those again were more sensitive to NMDA. We could block all of the apoptosis created by the NMDA exposure if we put in an inhibitor specific for the NMDA receptor subtype that we think is primarily involved in HD. It abolished the cell death both in the wild type and the mutant.

“We also found an activation of caspases enzymes that promote apoptosis,” she went on. “This caspase activation was much bigger with application of NMDA in the striatal HD mouse model than in the wild type. So there was a link between the rest of the HD research field, which is focusing more on the caspases effectors of the neuronal cell death in HD. And we were looking at what we think is an upstream trigger of increased NMDA receptor activity that occurs very early in the life of this mouse, and perhaps in people who are carrying the gene. This could in turn increase caspase activity, and so promote cell death.”

Initial Clinical Goal: Slow Down Disease

“Being a neurologist who sees HD patients in a clinic that Michael Hayden established here, and having been involved in some clinical trials in the past, the next step I would like to do in collaboration with his lab is to look at the specific inhibitors of NMDA receptors,” Raymond said. “We can give them orally to the mice early in life, perhaps immediately after weaning. Then we’d compare them at different time points in relation to their cohorts that aren’t getting the drug, for specific HD signs like changes in behavior and neuronal degeneration in the brain.

“This might be an effective therapy that we could then potentially bring to the clinic,” Raymond suggested. “Our primary goal would be to delay onset of Huntington’s disease.”