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A Common Path May Underlie
Most Motor Neuron Disease, Study Says The idea that motor neuron diseases like ALS tap into a common biology appeals to medical researchers. It makes sense: dying motor neurons look and behave very much alike, no matter what the disease. And it's a hot area of study because it could yield specific targets for therapy that could shut off cell death like a switch, in a variety of diseases. Now a Packard Center research team has strengthened the case for a common toxic path, using mice that model the motor neuron disease, transverse myelitis (TM). The scientists have focused specifically on excitotoxic reactions in cells — those caused by an excess of the nerve transmitter glutamate. Such reactions lead to cell injury and death. "We know excitotoxic injury likely plays a role in ALS," says Center researcher Douglas Kerr. Several dozen studies in the last decade say so, including research that paints motor neurons as especially vulnerable to this sort of damage. "And although ALS triggers are distinct and varied," Kerr adds, "they trip a common, fundamental process in excitotoxic injury. This new study gives us a hand in understanding how it works." The report from the Packard Center team, which includes graduate student Jessica Darman, appeared in the August issue of The Journal of Neuroscience. In clarifying steps along the excitotoxic path, the work suggests clear targets for therapy. Indeed, one arm of it shows successful blocking of nerve injury in a mouse model. In their study, the scientists infected mice and rats with a form of Sindbis virus, a nerve-infecting germ whose effects mirror both TM, which causes a sudden loss of motor function below the waist, and West Nile virus in humans. The researchers then examined the animals' spinal cord tissues at intervals after infection, both for the presence of virus and for signs of excitotoxic injury. The first find was that a large proportion of the motor neurons — some 80 percent — died even though they weren’t virus-infected. "This suggests that they may be innocent bystanders that got in the way of a wave of toxicity," Kerr explains. Center researchers Don Cleveland and Larry Goldstein drew a similar conclusion last year in the SOD1 mouse model of ALS. The second was that glutamate plays a large part in that toxic wave. In lab cultures of the neurons, chemically blocking glutamate’s entry more than doubled the number of surviving motor neurons. That was also true in live animals given a glutamate-blocker. There, all the neurons survived. Also, in live, infected animals given an agent that keeps the body from clearing glutamate away, far more motor neurons died than without the agent. Further study by the team suggests what may be going on: that the virus somehow cripples normal cell uptake of excess glutamate in the spinal cord. Indeed, their results showed a sharp drop in the molecules that normally ferry glutamate out of harm’s way. Finally, the researchers showed that minocycline, a drug currently under investigation in ALS circles, protects the animals well from hindlimb weakness. In the mice that got it, the team measured greatly increased ability to clear glutamate. “The idea that motor neurons are simply hapless victims of the excitotoxic process — that they don’t initiate it — is growing,” says Kerr. “Our study lends visibility to the perpetrators of the damage.” Funding for this study was from The Robert Packard Center for ALS Research at Johns Hopkins and the Muscular Dystrophy Association in addition to NIH grants. The research team includes Center scientists Nicholas Maragakis and Jeffrey Rothstein. |
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