Nerve Degeneration Pathway Discovered

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MADISON - A fruit fly model of ataxia telangiectasia (A-T) developed at the University of Wisconsin School of Medicine and Public Health has helped clarify a long-standing mystery: the cause of crippling nerve degeneration that is the hallmark of the disease. It is the first model to accurately mimic neuro-degeneration seen in human A-T.
The findings, reported in the May 1, 2008, issue of Genes and Development, suggest possible treatment options and may have important implications for other neuro-degenerative disorders, including Alzheimer’s disease.
A-T is a rare childhood disorder that damages the part of the brain that controls movement and speech. Initial signs usually appear during the first decade of life, with complete debilitation often occurring by the teenage years. About 20 percent of A-T patients develop fatal cancers, and many of them are acutely sensitive to radiation, such as X-rays.
David Wassarman and Randal Tibbetts, both associate professors in the Department of Pharmacology, combined their respective laboratories’ expertise in fruit fly genetics and the molecular biology of A-T for the project. The resulting A-T fruit fly, in which expression of the gene ATM (Ataxia telangiectasia mutated) is knocked down by RNA interference, allowed them to identify genes that are directly involved in preventing or promoting A-T-associated nerve degeneration.

For the study, Wassarman’s graduate student, Stacey Rimkus, screened 650 of the 13,000 genes contained in the fruit fly, looking for those that affect nerve degeneration in the absence of ATM.
“Everybody thought that only a single gene was involved in A-T, but we hypothesized that several were involved because symptoms in people with A-T vary greatly,” says Wassarman. Wide variations occur in the severity of symptoms and the time they occur in life.
Rimkus found three genes that partially curb progressive nerve death in the fly and three that worsen it. She then concentrated on a gene called String; the corresponding gene in humans and other organisms is called CDC25.
“String/CDC25 is known to play a role in the regulation of the cell cycle,” explains Wassarman. “It activates the transition from one stage in the cycle to the next.”

The ongoing cycle for most cells involves an initial growth phase, G1, followed by a period of DNA replication, or S phase, followed by another growth phase, called G2. Then cell division, or mitosis, occurs. Once nerve cells are formed, however, they do not go through the cell cycle.
The SMPH researchers theorized that due to gene mutations in A-T, neurons re-enter the cell cycle, and this abnormal behavior somehow signals them to die.
To test the theory, Rimkus removed String/CDC25 from A-T flies and found nerve degeneration to be less severe.
"By getting rid of this activator that was telling neurons to re-enter the cell cycle, we prevented that movement, which in turn prevented the neurons from dying,” Wassarman says. A fly—or person—in which ATM functions normally keeps neurons from re-entering the cell cycle.
Cell-cycle inhibitors for other diseases, such as cancer, are already on the market, notes Wassarman.
“In theory, if you could target String/CDC25 with one of these inhibitors in neurons, you could prevent neurons from dying in patients with A-T,” he says.
Knowledge gained from the current study may also shed light on other related diseases.
“In fly and mammal models for Alzheimer’s disease, evidence suggests that neurons are re-entering the cell cycle,” he says.
The cells may be reacting to stress caused by the plaques that are characteristic of Alzheimer’s, forcing them to re-enter the cell cycle and try to repair the problem.

Date Published: 05/01/2008

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