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CENTER SCIENTIST SPOTS ANOTHER MAJOR PATH
IN ALS MODEL The study, which uses mouse models of ALS, appears in the March 15 Journal of Neuroscience. It was funded by The Robert Packard Center for ALS Research at Johns Hopkins and by the Canadian Institutes of Health Research. The work centers on a family of molecules called CDKs (for cyclin-dependent kinases), which normally either help signal cells to divide or help regulate nervous system development. CDKs are active in growing animals. They get shut off in cells that no longer undergo mitosis, like motor neuron cells. "Problems may arise if CDKs become active in cells where they're meant to be quiescent," says McGill University biochemist Jean-Pierre Julien, Ph.D., who oversaw the research team. "We know that if you abnormally activate them in cultures of nerve cells, those cells die pretty handily," he says. "Now we've gone on to show that in animal models of ALS, whose nerve cells also die, those same CDK molecules are also abnormally active." Julien's team studied SOD1 mice, a standard animal model of the disease. These animals carry copies of a human gene that sparks a rare genetic form of ALS. Like humans, SOD1 mice undergo progressing muscle weakness and death. By using sensitive tracers, the researchers showed levels of most CDKs were significantly higher in SOD1 mice than in healthy ones. Two of the CDKs are especially crucial, Julien says, because, activated abnormally, they apparently trip cell suicide programs that quickly bring about cell death. What starts it all? Scientists know cell stress; inflammation and abnormal cell chemistry in general can raise CDKs in cells. Julien speculates something similar, like inflammation, may spark the CDK upswing in the mice. Interestingly, he says mice given the drug minocycline, an antibiotic that reduces inflammation, experience less CDK uproar in their cells. "Inhibitors of CDKs, which we already know are protective in other neurodegenerative conditions," Julien adds, "might give us a reasonable avenue to explore for ALS treatment." In fact, other Packard-funded scientists are now exploring CDK inhibition as future therapy for ALS. Other scientists in the study were Minh Dang Nguyen, Mathiew Boudreau, Jasna Kriz, Sébastien Couillard-Després, Holger Patzke, Michael Ahlijanian and David Kaplan. |
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