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School of Medicine
Johns Hopkins Medicine
Office of Corporate Communications
Media Contact: Joanna Downer
July 7, 2005
CANCER GENE CONTROLS NERVE CELL DEATH IN HUNTINGTON'S DISEASE
Johns Hopkins scientists have discovered that a gene well known for its role in promoting cancer also helps cause nerve cell death in Huntington's disease, a fatal disease in which specific brain cells gradually die. The discovery is described in the July 7 issue of Neuron.
An important advance in the basic understanding of Huntington's disease, the scientists' discovery may lead to new approaches to combating the disease. The researchers caution that any clinical application based on discovery of the cancer protein's involvement in Huntington's disease is likely a decade away or longer. Whether the cancer protein, called p53, is involved in other neurological diseases is unknown.
By examining cells from mice and people with the genetic mutation behind Huntington's disease, the researchers discovered that the faulty huntingtin [sic] protein binds to and overstimulates a protein called p53. The overactive p53 causes cells to churn out too much of a variety of other proteins, some of which help cause the cell's death by interfering with the cell's energy-producing factory, the mitochondria. Just like a factory would have to shut down if its power plant failed, cells shut down when their mitochondria stop working.
"Our discovery is the first to explain how the genetic problem behind Huntington's disease leads to the failure of mitochondria and the cells' eventual death," says Akira Sawa, M.D., Ph.D., an assistant professor at Johns Hopkins in the Department of Neuroscience and in the Department of Psychiatry's neurobiology program. "With more work, we should be able to find new ways to try to prevent the affected brain cells from dying."
Since 1993, scientists have known that a specific mutation in a gene dubbed huntingtin underlies Huntington's disease. The genetic mutation leads to production of a mutant protein, which gets chopped into pieces and accumulates in the nucleus of cells. Although scientists knew that accumulation of mutant huntingtin bits led to mitochondrial failure and to cell death, no one knew how.
Because p53 was known to control some genes involved in mitochondrial activity, Sawa, graduate student Byoung-Il Bae and postdoctoral fellow Hong Xu and their colleagues decided to see whether the mutant huntingtin protein might affect p53's activity.
The researchers discovered that in mouse and human cells containing the mutant huntingtin protein, levels of p53 were much higher than normal. Furthermore, they discovered that the mutant huntingtin directly binds to p53 and increases its activity, rather than acting through intermediaries. The overactive p53, in turn, stimulates overproduction of a host of other genes.
In experiments with mice carrying the Huntington's disease mutation, the researchers showed that excess p53 is responsible for disease-associated problems with motor control and cognition. Huntington's disease mice that also lacked p53 were spared the negative effects of the huntingtin mutation.
"Clinically, blocking p53 isn't an option for treating Huntington's disease, because we know that might cause cancer by allowing cells to keep dividing when they ought to die," Sawa points out. "But if one of the genes it controls is involved only in damaging the mitochondria in brain cells that die in Huntington's disease, perhaps it could be a useful target to try to prevent the death of those cells."
The researchers were funded by the National Institute of Mental Health, the National Eye Institute, the National Institute on Drug Addiction, the Huntington's Disease Society for America, the Hereditary Disease Foundation, the Stanley Medical Research Institute, the National Alliance for Research on Schizophrenia and Depression (NARSAD), S-R and the Korea Foundation for Advanced Studies.
Authors on the paper are Byoung-Il Bae, Hong Xu, Shuichi Igarashi, Masahiro Fujimuro, Nishant Agrawal, Diane Hayward, Timothy Moran, Craig Montell, Christopher Ross, Solomon Snyder and Akira Sawa, all of Johns Hopkins; and Yoichi Taya of the National Cancer Center Research Institute, Tokyo, Japan.
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