Sci. Aging Knowl. Environ., 7 December 2005
Tapping Into Renewal
Compound that boosts cell division slows Huntington's disease in mice
Unlock your latent abilities, and you could have abs of steel or make a fortune in real estate--or so the late-night infomercials promise. Hyped sales pitches aside, plugging into underutilized talents could help the brain resist the devastation of Huntington's disease (HD). A new study shows that cranking up the organ's capacity to produce neurons delays the disease's progress in mice. The work could lead to a therapy for this untreatable illness.
The symptoms of HD, which include uncontrolled movements, memory loss, and mood swings, usually begin when patients are in their 30s or 40s (see Huntington's Disease Case Study). The illness, which usually takes 1 to 3 decades to kill, stems from a fault in the protein huntingtin: Sufferers carry extra copies of the amino acid glutamine at one end of it. How this extended version injures the brain isn't clear, but neurons of HD patients amass globs of the protein and perish (see Rubinsztein Perspective). Hard-hit by this cell die-off is the striatum, a part of the brain that helps manage movement. The brain makes some replacement cells but not enough. One possible strategy for fighting HD involves spurring the organ to pump out more. Previous studies suggested that fibroblast growth factor 2 (FGF-2) is necessary for brain cell division and protects neurons in the lab dish. Neuroscientist Lisa Ellerby of the Buck Institute for Age Research in Novato, California, and colleagues tested whether this molecule spurs neuron production in rodents with an HD-like illness.
The researchers injected FGF-2 into genetically altered mice that manufacture a fragment of huntingtin bearing extra glutamines. Like people with HD, the rodents lose brain cells, become clumsy, and die. FGF-2 doses more than doubled cell formation in one of the brain nurseries where neurons are born. New neurons sported a marker that indicates they were migrating to damaged brain areas. Like normal cells in the striatum, the fresh ones sprouted branches that extend to a nearby structure. FGF-2 also stretched the amount of time the rodents could balance on a rotating rod and increased their life span by 20%, the researchers found. Moreover, the brains of mice injected with the growth factor harbored fewer of the huntingtin-containing knots. Additional cell culture experiments showed that FGF-2 slashed the death rate of neurons that fashion faulty huntingtin. The results "show that you can produce new neurons that are functional, in the sense that they form connections," says Ellerby. Now scientists must learn how to fine-tune the process so that it generates enough replacement cells, she says.
The study establishes that FGF-2 provides a dual benefit--spurring cell division and sheltering neurons--says geneticist David Rubinsztein of Cambridge University in the U.K. "The potential for treatment is high," says neuroscientist William Yang of the University of California, Los Angeles. For instance, he notes, delivering FGF-2 doesn't require anything fancier than a shot because the compound can enter the brain from the bloodstream. Although the work suggests that new cells link to existing ones, both scientists caution that researchers still need to establish that fresh neurons fire meaningful messages in brain circuits. They also warn that long-term use of FGF-2 could be risky because it promotes cancer. Further work might reveal whether helping the brain unleash its powers of self-renewal can keep HD at bay.
December 7, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150