January 28, 2002
MEDIA CONTACT: Joanna Downer
PHONE: 410-614-5105
E-MAIL: jdowner1@jhmi.edu

New Transgenic Rat Model of ALS Expands Research Possibilities

A team of scientists led by drug maker Wyeth-Ayerst and Johns Hopkins have engineered and tested a new rat model of Lou Gehrig's disease they say is far easier to work with than earlier mouse models.

Because of their larger size, the rats should expedite evaluation of novel treatments, such as those using stem cells, as well as deepen understanding of the fatal disease also known as amyotrophic lateral sclerosis (ALS), the scientists say. The "transgenic" rat, which carries a human gene, already has revealed the important role played by brain cells called astrocytes, a role obscured in mice.

The ALS rat, believed to be the first transgenic rat model of a neurodegenerative disease, moves from onset of symptoms through to ALS-like disability more quickly than ALS mice, making changes in cells in the rats more striking from day to day, the scientists report in the Jan. 29 online edition of the Proceedings of the National Academy of Sciences.

"The transgenic rats are a powerful tool," says neurologist Jeffrey Rothstein, M.D., director of the Center for ALS Research at Johns Hopkins and an author of the report. "Mice are just too small, for example, for reliable infusions into their spinal cords, the direction research on stem cell treatment is heading."

Scientists at Wyeth-Ayerst engineered the rats to carry an abnormal human gene for superoxide dismutase (SOD1), an enzyme that normally breaks down free radicals, highly reactive molecules that quickly damage DNA and kill cells. Faulty SOD1 behavior, caused by a number of different genetic mutations, is at the root of roughly one-fifth of inherited ALS cases.

The SOD1 rats, like the SOD1 mice before them, develop a disease very similar to ALS in humans, which is characterized by the death of motor nerve cells throughout the central nervous system. The rats are "symptom-free" for a longer time, but then deteriorate much more rapidly than the mice.

While the faster disease progression in rats might hide subtle effects of some potential treatments, the scientists point to the benefit of a model that can easily test stem cells and advance understanding of the disease. Stem cells are primitive precursors to other cells; embryonic stem cells can become any cell in the body, while so-called "adult" stem cells, like neuronal stem cells, are naturally destined to become the cells of a particular tissue.

So far, the new rat has revealed that specialized brain cells called astrocytes play a key role in the early steps of the disease. Astrocytes, which make up more than 50 percent of the brain's tissue, normally bridge the blood vessels and neurons in the brain.

In these rats, before physical symptoms develop and for reasons unknown, the main transporter for the neuron-exciting messenger glutamate begins disappearing from the astrocytes. Rothstein suggests the loss of the glutamate transporter may be an important step leading to the death of motor neurons, deaths that directly correspond to symptoms like limb paralysis.

Glutamate excites neurons, whipping them into a frenzy. The glutamate transporter in astrocytes helps maintain an appropriate balance of glutamate outside the neurons so these key brain cells aren't over-stimulated. When the transporter in astrocytes begins disappearing, glutamate builds up outside the cells, and hence outside neurons, leading to "glutamate toxicity," suggests Rothstein.

"Our idea is that over-stimulation of neurons by glutamate can lead to the neurons' deaths, and we continue to uncover evidence supporting this hypothesis," he says. "That the SOD1 rats already have revealed what is likely a key step in the disease process bodes well for the future of this model."

How mutant SOD1 directly injures a cell is still a mystery, but the rat model should help scientists determine how the faulty enzyme leads to disease, says Rothstein. In the central nervous system of human patients and SOD1 transgenic mice and rats, globs of faulty SOD1 proteins are found. Scientists know that loss of SOD1 function isn't to blame for the symptoms of ALS; instead, the faulty enzyme picks up a new, still unknown, function.

Finding the link between faulty SOD1 and the disappearing glutamate transporter should help clarify why the many SOD1 mutations appear in patients with inherited ALS and as well as the more common non-inherited form of the disease, says Rothstein

The investigations were stimulated by The ALS Association, and funded by the National Institutes of Health, the Center for ALS Research at Johns Hopkins, the Spinal Cord Disease Foundation and the Ludwig Institute for Cancer Research. The Center for ALS Research at Johns Hopkins, formed in March 2000, is a collaboration of scientists worldwide rapidly working to develop new treatments and to find a cure for ALS.

Other authors on the study are principal investigator David Howland, Yijin She, Beth Goad, Jamie Erickson, John Kulik, Lisa DeVito, George Psaltis and Louis DeGennaro of Wyeth-Ayerst; Jian Liu and Don Cleveland of the University of San Diego and the Center for ALS Research at Johns Hopkins; and Nicholas Maragakis and Benjamin Kim of Johns Hopkins School of Medicine and the Center for ALS Research at Johns Hopkins.


Related Web Site:
http://www.pnas.org



-- JHMI --
Search Press Releases

-----------------------------------------
News Media Home | Hopkins Medicine Home